Pharmacologically active 4-[2-hydroxy-4-(substituted)phenyl]naphthalen-2(1H)-ones and 2-ols, derivatives thereof and intermediates therefor

ABSTRACT

Compounds having the formula ##STR1## wherein ##STR2## R 1  is hydrogen, benzyl or alkanoyl, X is C 2-4  alkylene; and 
     Z-W is alkyl, phenylalkyl or pyridylalkyl which can have an oxygen atom as part of the alkyl chain and their use as CNS agents, antidiarrheals and antiemetics. Processes for their preparation and intermediates therefor are described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of Ser. No. 651,541, filed Sept. 17,1984, now U.S. Pat. No. 4,593,131, which is a division of applicationSer. No. 326,952, filed Dec. 2, 1981, now U.S. Pat. No. 4,486,609,issued Dec. 4, 1984, which in turn is a division of application Ser. No.244,435, filed Mar. 16, 1981, now U.S. Pat. No. 4,331,602, issued May25, 1982, which in turn is a division of application Ser. No. 189,402,filed Sept. 19, 1980, now U.S. Pat. No. 4,285,867, issued Aug. 25, 1981.

BACKGROUND OF THE INVENTION

This invention relates to novel4-[2-hydroxy-4-(substituted)phenyl]-naphthalen-2(1H)-ones and 2-ols, toderivatives thereof, to processes for preparation of said compounds, andintermediates therefor. The naphthalen-2(1H)-one and 2-ol products areuseful as CNS agents, especially as non-narcotic analgesics, antiemeticsand antidiarrheals.

Despite the current availability of a number of analgesic agents, thesearch for new and improved agents useful for the control of broadlevels of pain and accompanied by a minimum of side-effects continues.The most commonly used agent, aspirin, is of no practical value for thecontrol of severe pain and is known to exhibit various undesirableside-effects. Other analgesic agents, such as meperidine, codeine, andmorphine, possess addictive liability. The need for improved and potentanalgesic agents is, therefore, evident.

Compounds having utility as analgesics, tranquilizers, sedatives,antianxiety agents and/or as anticonvulsants, diuretics andantidiarrheal agents are described in Belgian Pat. Nos. 870,404 and870,402, both granted Mar. 12, 1979. Belgian Pat. No. 870,404 describes3-[2-hydroxy-4-(substituted)phenyl]cycloalkanones and cycloalkanols; andBelgian Pat. No. 870,402 discloses certain 2-(acyclicsubstituted)phenols; namely, 2-(hydroxyalkyl)-4-(substituted)phenols and2-(oxoalkyl)-4-(substituted)phenols.

U.S. Pat. No. 3,576,887, issued Apr. 27, 1971, discloses a series of1-(1'-hydroxy)alkyl-2-(o-hydroxyphenyl)cyclohexanes which exhibitcentral nervous system depressant properties.

U.S. Pat. No. 3,974,157 describes 2-phenylcyclohexanones which can besubstituted in the phenyl ring with up to two alkyl, hydroxy or alkoxygroups as intermediates for preparation of1-(aminoalkyl)-2-phenylcyclohexanols useful as analgesics, localanesthetics and antiarrhythmics.

Chemical Abstracts 85, 176952f (1976) discloses a number of 3-phenyl-and 3-phenylalkylcyclohexanones as intermediates for2-aminomethyl-3-phenyl (or phenylalkyl)cyclohexanones which exhibitanalgesic, sedative, antidepressant and anticonvulsant activities.

Our concurrently filed application, D.P.C. (Ph) 6302, entitled"Pharmacologically Active 2-Hydroxy-4-(Substituted)Phenyl Cycloalkanes,Derivatives and Intermediates Therefor" describes2-hydroxy-4-(substituted)cycloalkanones and cycloalkanols in which the4- (or 5)-position of the cycloalkyl moiety is substituted with hydroxyor a substituted alkyl group.

SUMMARY OF THE INVENTION

The compounds of this invention have the formula ##STR3## wherein A whentaken individually is hydrogen;

B when taken individually is hydroxy, or alkanoyloxy having from one tofive carbon atoms,

A and B when taken together are oxo;

R₁ is hydrogen, benzyl, or R₁ ' wherein R₁ ' is alkanoyl having from oneto five carbon atoms, P(O)(OH)₂ and mono- and disodium and potassiumsalts thereof, --CO(CH₂)₂ COOH and the sodium and potassium saltsthereof, and --CO(CH₂)_(p) NR₄ R₅ wherein p is 0 or an integer from 1 to4, each of R₄ and R₅ when taken individually is hydrogen or alkyl havingfrom one to four carbon atoms; R₄ and R₅ when taken together with thenitrogen to which they are attached form a 5- or 6-membered heterocyclicring (piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazinohaving from one to four carbon atoms in the alkyl group);

R₂ when taken individually is hydrogen,

R₃ when taken individually is hydrogen, methyl, hydroxy, hydroxymethyl,OR₁ ' or --CH₂ OR₁ ';

R₂ and R₃ when taken together are oxo, methylene or alkylenedioxy havingfrom two to four carbon atoms;

W is hydrogen, pyridyl or ##STR4## wherein W₁ is hydrogen, chloro orfluoro; when W is hydrogen, Z is

(a) alkylene having from five to thirteen carbon atoms; or

(b) --(alk₁)_(m) --O--(alk₂)_(n) -- wherein each of (alk₁) and (alk₂) isalkylene having from one to thirteen carbon atoms; each of m and n is 0or 1; with the provisos that the summation of carbon atoms in (alk₁)plus (alk₂) is not less than five or greater than thirteen; and at leastone of m and n is 1;

when W is other than hydrogen, Z is

(a) alkylene having from three to eight carbon atoms; or

(b) --(alk₁)_(m) --O--(alk₂)_(n) -- wherein each of (alk₁) and (alk₂) isalkylene having from one to eight carbon atoms; each of m and n is 0 or1; with the provisos that the summation of carbon atoms in (alk₁) plus(alk₂) is not less than three or greater than eight; and at least one ofm and n is 1.

Also included in this invention as noted above are the pharmaceuticallyacceptable acid addition salts of those compounds of formula I whichcontain a basic group. Typical of such compounds are those wherein the Wvariable is pyridyl and/or OR₁ represents a basic ester moiety. Incompounds having more than one basic group present, polyacid additionsalts are, of course, possible. Representative of such pharmaceuticallyacceptable acid addition salts are the mineral acid salts such as thehydrochloride, hydrobromide, sulfate, phosphate, nitrate; organic acidsalts such as the citrate, acetate, sulfosalicylate, tartrate,glycolate, malate, malonate, maleate, pamoate, salicylate, stearate,phthalate, succinate, gluconate, 2-hydroxy-3-naphthoate, lactate,mandelate and methanesulfonate.

Compounds having the above formula, and the pharmaceutically acceptableacid addition salts thereof, are effective as CNS agents, especially asanalgesics in mammals, including humans; and/or as anti-emetics inmammals, including man.

Compounds of formula I wherein A is hydrogen and B is hydroxy containasymmetic centers at the 2-, the 4-, the 4a-, and 8a- and the6-positions and may of course, contain additional asymmetric centers inthe --Z--W-- substituent of the phenyl ring. Cis-relationship betweenthe 2- and 4-position substituents of the bicyclic moiety is favored, asis trans-relationship between the 4a- and 8a-hydrogens, and between the4-hydrogen and the 4a-hydrogen because of their quantitatively greaterbiological activity. For the same reason, trans-relationships at the 4-,4a- and the 4a-, 8a-positions is favored for compounds wherein A and Bwhen taken together represent oxo. The 6-substituted compounds offormula I exhibit potent biological activity regardless of whether thestereochemistry at said position is axial or equatorial.

In addition to the compounds of formula I, various intermediates usefulin the preparation of said compounds are also included in thisinvention. The intermediates have formulae II-IV below: ##STR5## whereinR₆ is hydrogen or C₁₋₄ alkyl; ##STR6## and R₂ and R₃ are as previouslydefined. Also included in this invention are the ketoacids and theketoaldehydes corresponding to formula III and which are obtained bycleavage of the enolic lactone or lactol, respectively.

It is noted that formula I compounds wherein R₁ is benzyl are notpharmacologically active for the purposes disclosed herein but areuseful as intermediates to formula I compounds wherein R₁ is hydrogen.

For convenience, the above formula depicts the racemic compounds.However, formulae I-IV are considered to be generic to and embracive ofthe racemic modifications of the compounds of this invention, thediastereomeric mixtures, and pure enantiomers and diastereomers thereof.The utility of a racemic mixture, a diastereomeric mixture as well as ofthe pure enantiomers and diastereomers is determined by the biologicalevaluation procedures described below.

Favored because of their greater biological activity relative to that ofother compounds described herein are the compounds of formula I whereinA and B together are oxo; A and B when taken individually are hydrogenand hydroxy, respectively; R₂ is hydrogen, R₁ is hydrogen or alkanoyl;R₃ is hydrogen or hydroxymethyl; and Z and W have the values shownbelow:

    ______________________________________                                        Z             m      n     W                                                  ______________________________________                                        alkylene having from 7                                                                      --     --    H                                                  to 11 carbon atoms                                                            alkylene having from 4 to 7 carbon atoms                                                    --     --                                                                                   ##STR7##                                          (alk.sub.1).sub.mO(alk.sub.2).sub.n                                                         0,1    1                                                                                    ##STR8##                                          ______________________________________                                    

each of (alk₁) and (alk₂) is alkylene having from one to seven carbonatoms with the proviso the summation of carbon atoms in (alk₁) plus(alk₂) is not less than four or greater than seven;

    ______________________________________                                        (alk.sub.1).sub.mO(alk.sub.2).sub.n                                                          0,1         1     H                                            ______________________________________                                    

each of (alk₁) and (alk₂) is alkylene having from one to eleven carboncarbon atoms with the proviso the summation of carbon atoms in (alk₁)plus (alk₂) is not less than seven or greater than eleven.

Preferred compounds of formula I are those compounds of formula Iwherein

each of R₁ and R₂ is hydrogen;

Z is --C(CH₃)₂ (CH₂)₆ and W is hydrogen;

Z is C₄₋₇ alkylene and W is phenyl;

Z is --O-alkylene having 7 to 9 carbon atoms and W is hydrogen;

Z is --O-alkylene having from 4 to 5 carbon atoms and W is phenyl;

A is hydrogen and B is hydroxy (cis- and transforms);

A and B taken together are oxo;

R₃ =hydroxy or hydroxymethyl.

Especially preferred are the compounds of formula I wherein R₁, R₂, R₃,Z and W are as defined for the preferred compounds, A and B takenindividually are hydrogen and hydroxy, respectively and which haveformula I' ##STR9##

Additionally, the favored and preferred intermediates of formulae II-IVare those compounds having said formulae which serve as intermediatesfor the favored and preferred compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention having formula I are prepared byGrignard reaction of the appropriate 2-bromo-5-(Z-W-substituted)phenol,the hydroxy group of which is protected, with the appropriatehexahydronaphthalen-2(1H)-one of formula IV. The reaction isstereoselective and is illustrated in the following reaction sequence bythe conversion of a compound of formula IV-A (formula IV wherein R₂ +R₃=ethylenedioxy) to a compound of formula I-A. Preparation of2-bromo-5-(Z-W-substituted)phenol reactants is described in U.S. Pat.No. 4,147,872, issued Apr. 3, 1979. ##STR10##

Suitable protecting groups are those which do not interfere withsubsequent reactions and which can be removed under conditions which donot cause undesired reactions at other sites of said compounds or ofproducts produced therefrom. Representative of such protective groupsare methyl, ethyl and preferably benzyl or substituted benzyl whereinthe substituent is, for example, alkyl having from one to four carbonatoms, halo (Cl, Br, F, I) and alkoxy having from one to four carbonatoms; and dimethyl-t-butylsilyl. The ether protecting, or blocking,groups can be removed through the use of hydrobromic acid in acetic acidor hydrobromic acid, 48% aqueous. The reaction is conducted at elevatedtemperatures and desirably at the reflux temperature. However, when Z is--(alk₁)_(m) --O--(alk₂)_(m) --, acids such as polyphosphoric acid ortrifluoroacetic acid should be used to avoid cleavage of the etherlinkage. Other reagents such as hydriodic acid, pyridine hydrochlorideor hydrobromide, or lithio n-alkyl mercaptides inhexamethylphosphoramide can be used to remove protecting ether groupssuch as methyl or ethyl groups. When the protecting groups are benzyl orsubstituted benzyl groups, they can be removed by catalysthydrogenolysis. Suitable catalysts are palladium or platinum, especiallywhen supported on carbon. Alternatively they can be removed bysolvolysis using trifluoroacetic acid. A further procedure for removingbenzyl comprises treatment with n-butyllithium in a reaction-inertsolvent at room temperature. The dimethyl-t-butylsilyl group is removedby mild hydrolysis.

The exact chemical structure of the protecting group is not critical tothis invention since its importance resides in its ability to perform inthe manner described above. The selection and identification ofappropriate protecting groups can easily and readily be made by oneskilled in the art. The suitability and effectiveness of a group as ahydroxy protecting group are determined by employing such a group in theherein-illustrated reaction sequences. It should, therefore, be a groupwhich is easily removed to regenerate the hydroxy groups. Methyl andbenzyl are favored protecting groups since they are readily removed.

The protected 2-bromo-5-(Z-W substituted)phenol is then reacted withmagnesium in a reaction-inert solvent and generally in the presence of apromoter, e.g., cuprous salts such as the chloride, bromide and iodide(to promote 1,4-addition) with an appropriate compound of formula IV.Suitable reaction-inert solvents are cyclic and acyclic ethers such as,for example, tetrahydrofuran, dioxane and dimethyl ether of ethyleneglycol (diglyme). The Grignard reagent is formed in known manner, as,for example, by refluxing a mixture of one molar proportion of the bromoreactant and two molar proportions of magnesium in a reaction-inertsolvent, e.g. tetrahydrofuran. The resulting mixture is then cooled toabout 0° C. to -20° C., and cuprous iodide added followed by theappropriate formula IV compound at a temperature of from about 0° C. to-20° C. The amount of cuprous idodie used is not critical but can varywidely. Molar proportions ranging from about 0.2 to about 0.02 moles permole of bromo reactant afford satisfactory yields of compounds offormula I wherein the phenolic hydroxy group is protected (formula I, R₁=a protecting group; A+B=oxo, remaining groups as defined above).

The protected formula I compound is then treated with an appropriatereagent, if desired, to remove the protecting group. The benzyl group isconveniently removed by methods described above. If the protecting groupis an alkyl group (methyl or ethyl) it is removed by the above-mentionedmethods or by treatment with, for example, pyridine hydrochloride. Theketal group of formula I-A compounds is restored to oxo, if desired, bytreatment with acid to provide a compound of formula I-B.

However, in most instances in the processes for preparing compounds offormula I, the protecting groups are retained throughout the overallprocess and not removed until the penultimate or ultimate process stepis reached.

The compounds having formula I-C are prepared from the correspondingprotecting compounds of formula I-A by reduction. Sodium borohydride isfavored as reducing agent in this step since it not only affordssatisfactory yields of the desired product, but retains the protectinggroup on the phenolic hydroxy group, and reacts slowly enough withhydroxylic solvents (methanol, ethanol, water) to permit their use assolvents. Temperatures of from about -40° C. to about 30° C. aregenerally used. Lower temperatures, even down to -70° C., can be used toincrease selectivity of the reduction. Higher temperatures causereaction of the sodium borohydride with the hydroxylic solvent. Ifhigher temperatures are desired, or required for a given reduction,isopropyl alcohol or the dimethyl ether of diethylene glycol are used assolvents. Sometimes favored as reducing agent is potassium tri-sec-butylborohydride since it favors stereoselective formation of the2-beta-hydroxy derivative. The reduction is conducted in drytetrahydrofuran at a temperature below about -50° C. using equimolarquantities of the ketone compound and reducing agent.

Reducing agents such as lithium borohydride, diisobutylaluminum hydrideor lithium aluminum hydride which can also be used require anhydrousconditions and non-hydroxylic solvents, such as 1,2-dimethoxyethane,tetrahydrofuran, diethyl ether, dimethyl ether of diethylene glycol.

The deprotected compounds of formula I, except those of formulae I-E,wherein A is hydrogen and each of B and OR₁ is hydroxy can, of course,be obtained directly by catalytic reduction of the correspondingprotected compounds (formula I, A+B=oxo, R₁ =benzyl) overpalladium-on-carbon, or by chemical reduction of the unprotectedcompounds (formula I, A+B=oxo, R₁ =H) using the reducing agentsdescribed above. In practice it is preferred to produce the deprotectedcompounds of formula I (A=H, B=OH) by reduction of the correspondingbenzyl protected compounds of formula I (A+B=oxo, R₁ =benzyl) asdescribed above since it permits stereochemical control of the reductionand formation of the 2-beta hydroxy epimer (see conversion I-A to I-C)as the major product and thus facilitates separation and purification ofthe epimeric 2-hydroxy derivatives. The ketal group at the 6-position,if present, is converted to oxo by treatment with aqueous acid.Debenzylation of formulae I-E compounds is accomplished by reaction withn-butyllithium in hexane in order to avoid reduction of the 6-methylenegroup.

Compounds of formula I-C serve as intermediates for compounds of formulaI-D through I-G. Reduction of the oxo group by methods such as thosedescribed above affords the corresponding dihydroxy compound I-D.

Compounds of this invention wherein R₂ and R₃ taken together aremethylene (I-E) are readily prepared from the corresponding oxocompounds (I-C) via the Wittig reaction with methylenetriphenylphosphorane or other appropriate methylide. The usual procedurecomprises generating the Wittig reagent; that is, the methylide, in situand, immediately following generation of the methylide, reacting it withthe appropriate oxo compound. A convenient procedure for generating themethylide comprises reacting sodium hydride with dimethyl sulfoxide(sodium dimsyl) at a temperature of from about 50° C.-80° C., usuallyuntil evolution of hydrogen ceases, followed by reacting the resultingsolution with methyl triphenyl phosphonium bromide at a temperature offrom about 10° C. to about 80° C. To the thus-produced solution of theylide is then added the appropriate oxo compound and the mixture stirredat temperatures ranging from about room temperature to 80° C. Themethylene compound thus produced is isolated by known procedures.

Other methods of generating the methylide are, of course, known and canbe used in lieu of the above-described procedure. Typical procedures aredescribed by Maercker, Organic Reactions, 14, 270 (1965). In the oxocompounds having formula I-C, the phenolic hydroxy group can beprotected by groups other than benzyl if desired as, for example, byconversion to an alkanoyloxy derivative or to an ether such as, forexample, a tetrahydropyranyl ether. However, protection of the phenolichydroxy group is not absolutely necessary if sufficient base is presentto convert the phenolic hydroxy group to an alkoxide.

The methylene derivatives of formula I-E are reduced to correspondingmethyl derivatives (I-F) by catalytic hydrogenation. Simultaneousremoval of the benzyl protecting group also occurs.

Conversion of the methylene derivatives (I-E) to hydroxymethylderivatives (I-G) is accomplished by hydroboration-oxidation. Borane intetrahydrofuran is favored for the hydroboration step since it iscommercially available and gives satisfactory yields of the desiredhydroxymethyl compound. The reaction is generally conducted intetrahydrofuran or diethylene glycol dimethyl ether (diglyme). Theborane product is not isolated but is directly oxidized with alkalinehydrogen peroxide to the hydroxymethyl compound.

Compounds of formulae I-D, I-F and I-G wherein the 2-hydroxy group andthe R₃ substituent (OH, CH₃, CH₂ OH) have the beta configuration areresolved into their diastereomers by formation of the correspondingd-mandelates by reaction with d-mandelic acid. When R₃ is OH or CH₂ OH,the bis-d-mandelate derivative is formed. A convenient method ofpreparing the d-mandelates comprises reacting said formulae I-D, I-F andI-G compounds with an excess of d-mandelic acid in benzene in thepresence of p-toluenesulfonic acid monohydrate at the reflux withcontinuous removal of water. The diastereomeric mandelates thus preparedare separated via column chromatography on silica gel. Hydrolysis of theesters using potassium carbonate in methanol-tetrahydrofuran-wateraffords the enantiomeric I-D, I-F and I-G compounds.

Esters of formula I compounds wherein only group OR₁ is acylated areprepared by reacting formula I compounds wherein A together with Brepresent oxo and R₃ is other than hydroxy or hydroxymethyl with theappropriate alkanoic acid or acid of formula HOOC--(CH₂)_(p) --NR₂ R₃ inthe presence of a condensing agent such as dicyclohexylcarbodiimidefollowed by reduction of the oxo group to OH. Alternatively, they areprepared by reaction of a formula I compound with the appropriatealkanoic acid chloride or anhydride, e.g., acetyl chloride or aceticanhydride, in the presence of a base such as pyridine. The monoacylatedproduct is then subjected to further reactions, if desirable, such asreduction of A+B=oxo to the corresponding alcohol.

Diesters of formula I compounds in which each of B and OR₁ groups ishydroxy and R₃ is other than hydroxy or hydroxymethyl are prepared byacylation according to the above-described procedures. Compounds inwhich only the B-hydroxy group is acylated are obtained by mildhydrolysis of the corresponding diacyl derivative, advantage being takenof the greater ease of hydrolysis of the phenolic acyl group. Formula Icompounds in which only the phenolic hydroxy group is esterified areobtained by borohydride reduction of the corresponding formula I ketone(A+B=oxo) which is esterified at the phenolic hydroxy group. Thethus-produced formula I compounds in which only one OH group is acylatedcan then be acylated further with a different acylating agent to producea diesterified compound of formula I in which the ester groupsrepresented by B and OR₁ are different.

Diesters of compounds wherein each of OR₁ and B is hydroxy and R₃ ishydroxy or hydroxymethyl are also prepared by acylation of theappropriate trihydroxy containing derivative with at least threeequivalents of an appropriate acylating agent, e.g., acid chloride, acidanhydride or acid plus condensing agent, as described above. The orderof acylation of the hydroxy groups appears to be R₃ (═CH₂ OH)>OR₁ >B.This observation permits acylation of R₃ in the presence of OR₁ and B asOH. Diesters of formula I compounds in which each of OR₁ and R₃ isalkanoyloxy are prepared by acylating the appropriate formula I compoundwherein A+B is oxo and each of OR₁ and R₃ is hydroxy. The oxo (A+B)group is then reduced, if desired, by means of sodium borohydride. Thehydroxy group thus produced can be acylated with a different acylatingagent to produce a mixed ester containing product. Similarly, diestersof formula I compounds wherein each of OR₁, B is alkanoyloxy and R₃ ishydroxy are obtained by acylation of formula I compounds wherein R₂ +R₃is HO and each of OR₁ and B is hydroxy. Borohydride reduction of R_(2+R)₃ as oxo affords the desired diesters.

Acylation of a formula I compound wherein OR₁ and B is hydroxy and R₃ isOH or --CH₂ OH with one equivalent of an acylating agent affords amixture of esters wherein OR₁ and/or R₃ are acylated. The products areseparated chromatographically on silica gel.

Pharmaceutically acceptable acid addition salts of compounds of thisinvention are readily prepared by well known procedures. A typicalprocedure comprises reacting the appropriate formula I compound andappropriate acid, generally in stoichiometric amounts, in areaction-inert solvent, e.g. methanol, and recovering the resulting saltby a suitable method, e.g., filtration, precipitation by addition of anonsolvent such as ether, or evaporation of the solvent. When more thanone basic group is present, diacid salt formation becomes possible.

In the above sequence the oxo (or alkylenedioxy) group can be convertedto other values of R₂ and R₃ as defined herein at any step of thesequence if desired. It is generally advantageous for reasons of economyto carry out the sequence as illustrated and to convert thealkylenedioxy group to other values of R₂ and R₃ as shown in Sequence A.

The required compound of formula IV-A is prepared according to thefollowing reaction sequence. ##STR11##

In this sequence an appropriate 3-carboxycyclohex-3-enone is ketalizedusing an alkyleneglycol having from two to four carbon atoms accordingto procedures described above. The ketalized product is then esterifiedunder non-acid conditions such as by using dimethyl sulfate in thepresence of potassium carbonate. The unsaturated ester (VIII) is thenconverted to ketone II-A by reaction with metallated acetonedimethylhydrazone. The reaction comprises metallating thedimethylhydrazone of acetone by reaction with a suitable lithiatingagent such as n-butyllithium or lithium diisopropylamide in areaction-inert solvent such as tetrahydrofuran at 0° C. or lower. Thelithiated acetone dimethylhydrazone is then reacted with a solution ofcuprous idodide-diisopropylsulfide in tetrahydrofuran or otherreaction-inert solvent at a temperature of -78° C. to -50° C. Thetemperature of the reaction mixture is gradually warmed to about 0° C.over a period of one half to one hour and then cooled to about -78° C.The cuprate thus prepared is then reacted with the unsaturated esterVIII to produce the dimethylhydrazone of the ester of II-A. Oxidativehydrolysis of the dimethylhydrazone using, for example, aqueous sodiumperiodate at pH 7, or by means of cupric chloride inwater-tetrahydrofuran at pH 7 affords the ester of II-A. Hydrolysis(saponification) of the ester provides II-A.

Ketone II-A is transformed to the enolic lactone III-A by treatment withsodium acetate in acetic anhydride at an elevated temperature, e.g.,reflux. Other dehydrating conditions can, of course, be used.

The enol lactone is then treated with diisobutylaluminum hydride in areaction-inert solvent at a temperature of -20° C. or lower. Otheruseful reducing agents are lithium tri-sec-butyl hydride,9-borobicyclo[3.3.1]nonane, and lithium tri-tert-butoxyaluminohydride.The keto aldehyde thus produced, and which is in equilibrium with thecorresponding lactol (III-B) is then cyclized by intramolecular aldolcondensation using a secondary amine, preferably pyrrolidine, and aceticacid as catalysts to provide the bicyclic ketone (IV-A).

Alternatively, the compound of formula IV-A is preferably produced byreaction of decahydro-2,6-naphthalenedione monoethylene ketal withlithium diisopropylamide in a reaction-inert solvent, e.g.tetrahydrofuran, at an initial temperature of about -50° C. to -78° C.followed by warming to ambient temperature. The mixture is then cooledto -10° C. to +10° C. and treated with diphenyldisulfide. Oxidation ofthe 3-alpha-phenylthiodecahydro-2,6-naphthalenedione 6-monoethyleneketal thus produced with a peracid such as m-chloro-peroxybenzoic acidat 0° C. to 20° C. in a reaction-inert solvent (CH₂ Cl₂) affords thecorresponding phenylsulfenyl derivative. Said compound can be producedin a single step by reacting decahydro-2,6-naphthalenedione monoethyleneketal with an alkylphenylsulfinate in the presence of an alkali metalhydride at about 0° C. in diglyme.

Treatment of the phenylsulfinyl derviative with a solid base (CaCO₃) intoluene at 110° C. produces the compound of formula IV-A.

Also of value as CNS agents, anticonvulsants, antiemetics, analgesicsand antidiarrheal agents in the same manner as compounds of formula Iabove, are compounds of formula I wherein A is hydrogen and B ishydrogen, amino or acetamido; and R₁, R₂, R₃, Z and W are as defined informula I above.

Compounds of this invention wherein B is amino are prepared from thecorresponding compounds wherein A and B taken together represent oxo.One procedure comprises converting the appropriate oxo compound (ketone)of formula I to the corresponding oxime or oxime derivative; e.g., analkyl ether or an acetyl derivative, followed by reduction of the oximeor derivative thereof to the desired amine. Of course, when R₂ and R₃taken together represent oxo, said oxo group must be protected to avoidreaction at that site. The ketal (R₂ +R₃ =alkylenedioxy) group is apreferred protecting group because of the ease of preparation of saidcompounds and the relative ease of removal of said group to regeneratethe oxo group.

The oximes of compounds of formula I wherein A and B taken togetherrepresent oxo, and R₂ and R₃ taken together are other than oxo, areprepared by reacting said compounds with hydroxylamine hydrochloride ina solution of methanol-water at room temperature. In practice, it ispreferred to use an excess of hydroxylamine, up to as much as a threefold excess. Under such conditions the preparation of the desired oximederivative is complete in 1 to 2 hours. The product is isolated byaddition of the reaction mixture to water followed by basification to pH9.5 and extraction with a water-immiscible solvent such as ethylacetate.

When O-methylhydroxylamine hydrochloride is employed in place ofhydroxylamine hydrochloride, the reaction provides the O-methyloximederivative. When using O-methylhydroxylamine, it is preferred to extendthe reaction time to 6 to 12 hours. Isolation of the product is carriedout in the same manner as previously described for the oxime derivative.

Preparation of the O-acetyloxime compounds is accomplished byacetylation of the corresponding oxime with an equimolar amount ofacetic anhydride in the presence of an equimolar amount of pyridine. Theuse of an excess of the anhydride and pyridine aid in the completion ofthe reaction and an excess of two to three fold of each is preferred.The reaction is best conducted in an aprotic hydrocarbon solvent such asbenzene or toluene at room temperature overnight. On completion of thereaction, water is added and the product is separated in the hydrocarbonlayer. Alternatively, O-acetyl derivatives can be prepared by treatingthe requisite oxo compound with O-acetylhydroxylamine hydrochlorideunder reaction conditions similar to those described above forpreparation of the oxime derivatives.

The oxime or oxime derivative is then reduced catalytically using, forexample, Raney nickel, palladium-on-charcoal or platinum oxide at aninitial hydrogen pressure of about 2-3 atmospheres at ambienttemperature in a reaction-inert solvent such as C₁₋₄ alkanol, or lithiumaluminum hydride in a reaction-inert solvent such as tetrahydrofuran atreflux temperature.

A still further procedure comprises the Gabriel synthesis in whichpotassium phthalimide is reacted with a 4-halo, e.g. 4-iodo- or 4-bromoderivative of a compound of formula I (B=I, Br) and the resultingphthalimide derivative hydrolyzed with a base such as sodium orpotassium hydroxide or hydrazine. The 4-halo compound of formula I isprepared by reaction of the corresponding hydroxy compound of formulaI-C with phosphorous halide or hydrogen halide.

A favored procedure for preparing amino compounds of formula I comprisescondensation of the appropriate formula I compound wherein A and B takentogether represent oxo with the ammonium salt of a lower alkanoic acidand subsequent reduction of the in situ generated imine. In addition tolower alkanoic acid ammonium salts, ammonium salts of inorganic acidscan also be used in this procedure.

A further favored procedure comprises reaction of the appropriatecompound of formula I wherein B is alpha-hydroxy with equimolarquantities of phthalimide, triphenylphosphine anddiethylazodicarboxylate.

In practice, a solution of the ketone (A+B=O) in a lower alkanol such asmethanol is treated with an ammonium salt of an alkanoic acid such asacetic acid and the cooled reaction mixture treated with the reducingagent sodium cyanoborohydride. The reaction is allowed to proceed atroom temperature for several hours, and is subsequently hydrolyzed andthe product isolated.

Although stoichiometric proportions of ketone and ammonium alkanoate arerequired, it is advantageous to use up to a ten fold excess of ammoniumalkanoate in order to ensure rapid formation of the imine. It is alsoadvantageous to conduct the reduction at ambient temperature and to usetwo moles of sodium cyanoborohydride per mole of ketone reactant inorder to maximize yield of the final product. Reaction is complete in2-3 hours.

Reduction of the imine can, of course, be carried out with otherreducing agents such as palladium-on-charcoal. In practice, a solutionof the appropriate ketone in a lower alkanol, such as methanol orisopropanol, is treated with an ammonium alkanoate, such as ammoniumacetate, and 10% palladium-on-charcoal, and the resulting suspensionshaken in a hydrogen atmosphere at temperatures of about 25°-50° C.until the theoretical amount of hydrogen has been absorbed. It ispreferred that a 10 fold excess of the ammonium alkanoate be employed toensure complete reaction in a reasonable time period. The amount of thecatalyst can vary from 10% to 50% on a weight basis, of the startingketone. The initial pressure of the hydrogen is not critical, and apressure from one to fifty atmospheres is preferred to shorten thereaction time. Employing the aforementioned parameters, the reactiontime will vary between 2 to 6 hours. Upon completion of the reductiveamination reaction, the spent catalyst is filtered and the filtrateconcentrated to dryness.

The amino compounds produced by the above procedures are isolated bytaking advantage of their basic nature which permits convenientseparation from non-basic by-products and reactants. In general, anaqueous solution of the product is extracted over a range of graduallyincreasing pH so that non-basic materials are removed at the lower pH'sand the product at a pH of about 9. The extracting solvents, e.g. ethylacetate, diethyl ether, are back-washed with brine and water, dried andevaporated to give the product.

Formula I compounds wherein each of A and B is hydrogen are preparedfrom corresponding compounds wherein A and B taken together are oxo. Theprocess comprises converting the oxo group to a hydrazone (orsemicarbazone) and then decomposing said hydrazone (or semicarbazone) byalkali such as sodium or potassium hydroxide to produce the desiredcompound wherein each of A and B is hydrogen. The process is readilycarried out by heating a mixture of the appropriate compound of formulaI wherein A and B taken together are oxo and R₂ and R₃ taken togetherare other than oxo with hydrazine hydrate in a reaction inert solventsuch as ethylene glycol or triethylene glycol at 100° C. Solid potassium(or sodium) hydroxide is then added and the mixture heated at anelevated temperature, e.g. 150°-200° C. It is then cooled, acidified andthe product recovered, e.g. by extraction with ether, or other knownmethod.

Esters of formula I compounds in which the amino group and/or hydroxygroups (OR₁, B, R₃) are acylated are prepared by acylation with theappropriate alkanoic acid or amino acid in the presence of a condensingagent such as dicyclohexylcarbodiimide or by reaction with theappropriate alkanoic acid chloride or anhydride, e.g. acetyl chloride oracetic anhydride, in the presence of a base such as pyridine.

When B is amino, further opportunity for formation of pharmaceuticallyacceptable acid addition salts exists and, when more than one basicgroup is present, to formation of poly-acid addition salts according toprocedures described herein.

The analgesic properties of the compounds of this invention aredetermined by tests using nociceptive stimuli.

TESTS USING THERMAL NOCICEPTIVE STIMULI (a) Mouse Hot Plate AnalgesicTesting

The method used is modified after Woolfe and MacDonald, J. Pharmacol.Exp. Ther., 80, 300-307 (1944). A controlled heat stimulus is applied tothe feet of mice on a 1/8-inch thick aluminum plate. A 250 wattreflector infrared heat lamp is placed under the bottom of the aluminumplate. A thermal regulator, connected to thermistors on the platesurface, programs the heat lamp to maintain a constant temperature of57° C. Each mouse is dropped into a glass cylinder (61/2-inch diameter)resting on the hot plate, and timing is begun when the animal's feettouch the plate. The mouse is observed at 0.5 and 2 hours aftertreatment with the test compound for the first "flicking" movements ofone or both hind feet, or until 10 seconds elapse without suchmovements. Morphine has an MPE₅₀ =4-5.6 mg./kg. (s.c.).

(b) Mouse Tail Flick Analgesic Testing

Tail flick testing in mice is modified after D'Amour and Smith, J.Pharmacol. Exp. Ther., 72, 74-79 (1941) using controlled high intensityheat applied to the tail. Each mouse is placed in a snug-fitting metalcylinder, with the tail protruding through one end. This cylinder isarranged so that the tail lies flat over a concealed heat lamp. At theonset of testing an aluminum flag over the lamp is drawn back, allowingthe light beam to pass through the slit and focus onto the end of thetail. A timer is simultaneously activated. The latency of a sudden flickof the tail is ascertained. Untreated mice usually react within 3-4seconds after exposure to the lamp. The end point for protection is 10seconds. Each mouse is tested at 0.5 and 2 hours after treatment withmorphine and the test compound. Morphine has an MPE₅₀ of 3.2-5.6 mg./kg.(s.c.).

(c) Tail Immersion Procedure

The method is a modification of the receptacle procedure developed byBenbasset, et al., Arch. int. Pharmacodyn., 122, 434 (1959). Male albinomice (19-21 g.) of the Charles River CD-1 strain are weighed and markedfor identification. Five animals are normally used in each drugtreatment group with each animal serving as its own control. For generalscreening purposes, new test agents are first administered at a dose of56 mg./kg. intraperitoneally or subcutaneously, delivered in a volume of10 ml./kg. Preceding drug treatment and at 0.5 and 2 hours post drug,each animal is placed in the cylinder. Each cylinder is provided withholes to allow for adequate ventilation and is closed by a round nylonplug through which the animal's tail protrudes. The cylinder is held inan upright position and the tail is completely immersed in the constanttemperature waterbath (56° C.). The endpoint for each trial is anenergetic jerk or twitch of the tail coupled with a motor response. Insome cases, the endpoint may be less vigorous post drug. To preventundue tissue damage, the trial is terminated and the tail removed fromthe waterbath within 10 seconds. The response latency is recorded inseconds to the nearest 0.5 second. A vehicle control and a standard ofknown potency are tested concurrently with screening candidates. If theactivity of a test agent has not returned to baseline values at the2-hour testing point, response latencies are determined at 4 and 6hours. A final measurement is made at 24 hours if activity is stillobserved at the end of the test day.

TEST USING CHEMICAL NOCICEPTIVE STIMULI Suppression ofPhenylbenzoquinone Irritant-Induced Writing

Groups of 5 Carworth Farms CF-1 mice are pretreated subcutaneously ororally with saline, morphine, codeine or the test compound. Twentyminutes (if treated subcutaneously) or fifty minutes (if treated orally)later, each group is treated with intraperitoneal injection ofphenylbenzoquinone, an irritant known to produce abdominal contractions.The mice are observed for 5 minutes for the presence or absence ofwrithing starting 5 minutes after the injection of the irritant. MPE₅₀'s of the drug pretreatments in blocking writhing are ascertained.

TESTS USING PRESSURE NOCICEPTIVE STIMULI Effect on the Haffner TailPinch Procedure

A modification of the procedure of Haffner, Experimentelle PrufungSchmerzstillender. Deutch Med. Wschr., 55, 731-732 (1929) is used toascertain the effects of the test compound on aggressive attackingresponses elicited by a stimulus pinching the tail. Male albino rats(50-60 g.) of the Charles River (Sprague-Dawley) CD strain are used.Prior to drug treatment, and again at 0.5, 1, 2 and 3 hours aftertreatment, a Johns Hopkins 2.5-inch "bulldog" clamp is clamped onto theroot of the rat's tail. The endpoint at each trial is clear attackingand biting behavior directed toward the offending stimulus, with thelatency for attack recorded in seconds. The clamp is removed in 30seconds if attacking has not yet occurred, and the latency of responseis recorded as 30 seconds. Morphine is active at 17.8 mg./kg. (i.p.).

TESTS USING ELECTRICAL NOCICEPTIVE STIMULI The "Flinch-Jump" Test

A modification of the flinch-jump procedure of Tenen,Psychopharmacologia, 12, 278-285 (1968) is used for determining painthresholds. Male albino rats (175-200 g.) of the Charles River(Sprague-Dawley) CD strain are used. Prior to receiving the drug, thefeet of each rat are dipped into a 20% glycerol/saline solution. Theanimals are then placed in a chamber and presented with a series of1-second shocks to the feet which are delivered in increasing intensityat 30-second intervals. These intensities are 0.26, 0.39, 0.52, 0.78,1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3.04 mA. Each animal'sbehavior is rated for the presence of (a) flinch, (b) squeak and (c)jump or rapid forward movement at shock onset. Single upward series ofshock intensities are presented to each rat just prior to, and at 0.5,2, 4 and 24 hours subsequent to drug treatment.

Results of the above tests are recorded as percent maximum possibleeffect (%MPE). The %MPE of each group is statistically compared to the%MPE of the standard and the predrug control values. The %MPE iscalculated as follows: ##EQU1##

The compounds of this invention, when used as analgesics via oral orparenteral administration, are conveniently administered in compositionform. Such compositions include a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractics. For example, they can be administered in the form of tablets,pills, powders or granules containing such excipients as starch, milksugar, certain types of clay, etc. They can be administered in capsules,in admixtures with the same or equivalent excipients. They can also beadministered in the form of oral suspensions, solutions, emulsions,syrups and elixirs which may contain flavoring and coloring agents. Fororal administration of the therapeutic agents of this invention, tabletsor capsules containing from about 0.01 to about 100 mg. are suitable formost applications.

The physician will determine the dosage which will be most suitable foran individual patient and it will vary with the age, weight and responseof the particular patient and the route of administration. Generally,however, the initial analgesic dosage in adults may range from about 0.1to about 750 mg. per day in single or divided doses. In many instances,it is not necessary to exceed 100 mg. daily. The favored oral dosagerange is from about 1.0 to about 300 mg./day; the preferred dose is fromabout 1.0 to about 50 mg./day. The favored parenteral dose is from about0.1 to about 100 mg./day; the preferred range from about 0.1 to about 20mg./day.

This invention also provides pharmaceutical compositions, including unitdosage forms, valuable for the use of the herein described compounds asanalgesics and other utilities disclosed herein. The dosage form can begiven in single or multiple doses, as previously noted, to achieve thedaily dosage effective for a particular utility.

The compounds (drugs) described herein can be formulated foradministration in solid or liquid form for oral or parenteraladministration. Capsules containing drugs of this invention are preparedby mixing one part by weight of drug with nine parts of excipient suchas starch or milk sugar and then loading the mixture into telescopinggelatin capsules such that each capsule contains 100 parts of themixture. Tablets containing said compounds are prepared by compoundingsuitable mixtures of drug and standard ingredients used in preparingtablets, such as starch, binders and lubricants, such that each tabletcontains from 0.10 to 100 mg. of drug per tablet.

Suspensions and solutions of these drugs, particularly those wherein R₁(formula I) is hydroxy, are often prepared just prior to use in order toavoid problems of stability of the suspensions or solution (e.g.precipitation) of the drug upon storage. Compositions suitable for suchare generally dry solid compositions which are reconstituted forinjectable administration.

By means of the above procedures, the analgesic activity of severalcompounds of this invention is determined. The compounds have theformula shown below: ##STR12##

The following abbreviations are used in the Tables:PBQ=phenylbenzoquinone-induced writhing; TF=tail flick; HP=hot plate;RTC=rat tail clamp; and FJ=flinch jump.

                  TABLE I                                                         ______________________________________                                        Analgesic Activity - MPE, mg./kg.                                             Route = Subcutaneous.                                                         A        B        R.sub.2 R.sub.3 PBQ   RTC                                   ______________________________________                                        O             H       H         3.19  --                                       H        OH      H       H       1.46  13.4                                   H        OH      H       H       1.24  --                                     H        OH       H       OH     0.55  2.3                                    H        OH       H       OH     3.22  6.9                                    H.sup.(c)                                                                              OH       H       CH.sub.2 OH                                                                          0.054 0.22                                   H        OH       H       CH.sub.2 OH                                                                          2.81  6.8                                    H        OH        O           1.44  5.6                                      H.sup.(a)                                                                               OH      H       CH.sub.2 OH                                                                          0.018 0.06                                   H.sup.(b)                                                                              OH       H       CH.sub.2 OH                                                                          1.58  10                                    ______________________________________                                         .sup.(a) Pure enantiomer A                                                    .sup.(B) Pure enantiomer B                                                    .sup.(C) Analgesic activity by oral administration: PBQ = 0.25; RTC = 0.7     mg./kg                                                                   

The antiemetic properties of the compounds of formula I are determinedin unanesthetized unrestrained cats according to the procedure describedin Proc. Soc. Exptl. Biol. and Med., 160, 437-440 (1979).

The compounds of the present invention are active antiemetics via oraland parenteral administration and are conveniently administered incomposition form. Such compositions include a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice. For example, they may be administered in theform of tablets, pills, powders or granules containing such excipientsas starch, milk sugar, certain types of clay, etc. They may beadministered in capsules, in admixtures with the same or equivalentexcipients. They may also be administered in the form of oralsuspensions, dispersions, solutions, emulsions, syrups and elixirs whichmay containing flavoring and coloring agents. For oral administration ofthe therapeutic agents of this invention, tablets or capsules containingfrom about 0.01 to about 100 mg. are suitable for most applications.

The physician will determine the dosage which will be most suitable foran individual patient and it will vary with the age, weight and responseof the particular patient and the route of administration. Generally,however, the initial antiemetic dose of drug is administered in anamount effective to prevent nausea. Such dosage in adults may range from0.01 to 500 mg. per day in single or divided doses. In many instances,it is not necessary to exceed 100 mg. daily. The favored oral dosagerange is from about 0.01 to about 300 mg./day; the preferred range isfrom about 0.10 to about 50 mg./day. The favored parenteral dose is fromabout 0.01 to about 100 mg./day; the preferred range from about 0.01 toabout 20 mg./day.

Their antidiarrheal utility is determined by a modification of theprocedure of Neimegeers et al., Modern Pharmacology-Toxicology, Willemvan Bever and Harbans Lal, Eds., 7, 68-73 (1976). In general, the dosagelevels and routes of administration for use of these compounds asantidiarrheal agents parallels those with respect to their use asanalgesic agents.

The compounds (drugs) described herein can be formulated foradministration in solid or liquid form for oral or parenteraladministration. Capsules containing compounds of formulae I or II areprepared by mixing one part by weight of drug with nine parts ofexcipient such as starch or milk sugar and then loading the mixture intotelescoping gelatin capsules such that each capsule contains 100 partsof the mixture. Tablets are prepared by compounding suitable mixtures ofdrug and standard ingredients used in preparing tablets, such as starch,binders and lubricants, such that each tablet contains from 0.01 to 100mg. of drug per tablet.

In addition to these uses, the herein-described compounds also exhibitactivity as tranquilizers, sedatives, anticonvulsants, diuretics and asantianxiety agents.

EXAMPLE 13,4-alpha,4a-beta,5,6,7,8,8a-alpha-Octahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-naphthalen-2(1H)-one

A solution of 5.20 g. (13.4 mmole) of1-bromo-2-benzyloxy-4-(1,1-dimethylheptyl)benzene in 27 ml. oftetrahydrofuran is slowly added to 641 mg. (26.7 mmole) of magnesiummetal. After a 5 minute initiation period the rate of addition isadjusted such that reflux is just maintained. The reaction mixture isstirred 30 minutes longer while cooling to 25° C. It is then cooled to-15° C. and 127 mg. (0.668 mmole) of cuprous iodide is added. Theresultant mixture is stirred 5 minutes and then a solution of 1.8 g.(12.2 mmole) of trans-4a,5,6,7,8,8a-hexahydro-napthalen-2(1H)-one in 10ml. of tetrahydrofuran is added over a 10 minute period. Half waythrough the addition of the naphthalenone another 127 mg. (0.668 mmole)portion of cuprous iodide is added. The reaction mixture is stirred 5minutes longer and then added to 250 ml. of cold, saturated ammoniumchloride and 250 ml. of ether. The ether extract of the quenchedreaction is washed once with 250 ml. of saturated ammonium chloride,dried over magnesium sulfate and evaporated to an oil. The crude oil ispurified via column chromatography on 150 g. of silica gel eluted with10 ml. fractions with 15% ether-petroleum ether to yield 3.45 g. (62%)of the title compound as an oil.

IR (CHCl₃): 1724, 1626 and 1582 cm⁻¹.

MS (m/e): 460 (M.sup.⊕), 440, 375, 369, 363, 351 and 91.

PMR (CDCl₃): delta 0.88 (m, terminal methyl), 1.28 (s, gem dimethyls),5.12 (s, benzylic methylene), 6.90 (dd, J=8 and 2 Hz, ArH), 6.90 (d, J=2Hz, ArH), 7.12 (d, J=8 Hz, ArH) and 7.42 (s, PhH).

In like manner, the following compounds are prepared by substitutingequivalent amounts of the appropriate1-bromo-2-benzyloxy-4(substituted)benzenes for1-bromo-2-benzyloxy-4-(1,1-dimethylheptyl)benzene.

    __________________________________________________________________________     ##STR13##                                                                    Z              W      Z             W                                         __________________________________________________________________________    C(CH.sub.3).sub.2 (CH.sub.2).sub.4                                                           H      O(CH.sub.2).sub.7                                                                           H                                         (CH.sub.2).sub.8                                                                             H      OCH(CH.sub.3)(CH.sub.2).sub.9                                                               H                                         C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                           H      OCH(CH.sub.3)(CH.sub.2).sub.5                                                               H                                         (CH.sub.2).sub.7                                                                             H      OC(CH.sub.3).sub.2 (CH.sub.2).sub.5                                                         H                                         C(CH.sub.3).sub.2 (CH.sub.2).sub.8                                                           H      OC(CH.sub.3).sub.2 (CH.sub.2).sub.7                                                         H                                         CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2).sub.5                                                     H      O(CH.sub.2).sub.2 C(CH.sub.3).sub.2 (CH.sub.2).sub.2                          2             H                                         (CH.sub.2).sub.11                                                                            H      O(CH.sub.2).sub.4                                                                           C.sub.6 H.sub.5                           (CH.sub.2).sub.3                                                                             C.sub.6 H.sub.5                                                                      O(CH.sub.2).sub.6                                                                           C.sub.6 H.sub.5                           CH(CH.sub.3)(CH.sub.2).sub.5                                                                 C.sub.6 H.sub.5                                                                      OC(CH.sub.3).sub.2 (CH.sub.2).sub.3                                                         C.sub.6 H.sub.5                           CH(CH.sub.3 )(CH.sub.2).sub.3                                                                C.sub.6 H.sub.5                                                                      OCH(CH.sub.3)(CH.sub.2).sub.3                                                               C.sub.6 H.sub.5                           CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2).sub.3                                                     C.sub.6 H.sub.5                                                                      O(CH.sub.2).sub.4                                                                           4FC.sub.6 H.sub.4                         (CH.sub.2).sub.8                                                                             C.sub.6 H.sub.5                                                                      OCH(CH.sub.3)(CH.sub.2).sub.3                                                               4FC.sub.6 H.sub.4                         CH(CH.sub.3)(CH.sub.2).sub.3                                                                 4-FC.sub.6 H.sub.4                                                                   OCH(CH.sub.3)(CH.sub.2).sub.5                                                               4FC.sub.6 H.sub.4                         CH(C.sub.2 H.sub.5)(CH.sub.2).sub.4                                                          4-FC.sub.6 H.sub.4                                                                   O(CH.sub.2).sub.7                                                                           4ClC.sub.6 H.sub.4                        CH(O.sub.2 H.sub.5)(CH.sub.2).sub.2                                                          4-ClC.sub.6 H.sub.4                                                                  OCH(C.sub.2 H.sub.5)(CH.sub.2).sub.3                                                        4ClC.sub.6 H.sub.4                        (CH.sub.2).sub.5                                                                             H      O(CH.sub.2).sub.3                                                                           C.sub.6 H.sub.5                           (CH.sub.2).sub.13                                                                            H      O(CH.sub.2).sub.8                                                                           4-FC.sub.6 H.sub.4                        O(CH.sub.2).sub.5                                                                            H      OC(CH.sub.3).sub.2 (CH.sub.2).sub.5                                                         4-ClC.sub.6 H.sub.4                       O(CH(CH.sub.3)CH.sub.2                                                                       C.sub.6 H.sub.5                                                                      O(CH.sub.2).sub.13                                                                          H                                         CH(CH.sub.3)(CH.sub.2).sub.3                                                                 4-ClC.sub.6 H.sub.4                                                                  (CH.sub.2).sub.4 OCH.sub.2                                                                  C.sub.6 H.sub. 5                          (CH.sub.2).sub.4                                                                             4-pyridyl                                                                            (CH.sub.2).sub.6 O                                                                          C.sub.6 H.sub.5                           CH(CH.sub.3)(CH.sub.2).sub.3                                                                 4-pyridyl                                                                            CH(CH.sub.3)(CH.sub.2).sub.2 O                                                              C.sub.6 H.sub.5                           CH(C.sub.2 H.sub.5)CH.sub.2                                                                  4-pyridyl                                                                            CH(CH.sub.3)(CH.sub.2).sub.5 O                                                              C.sub.6 H.sub.5                           (CH.sub.2).sub.7                                                                             4-pyridyl                                                                            (CH.sub.2).sub.6 O                                                                          4-FC.sub.6 H.sub.4                        CH(CH.sub.3)CH(CH.sub.3)CH.sub.2                                                             4-pyridyl                                                                            (CH.sub.2).sub.6 O                                                                          4-ClC.sub.6 H.sub.4                       CH(CH.sub.3)CH(CH.sub.3)CH.sub.2                                                             3-pyridyl                                                                            (CH.sub.2).sub.3 OCH(CH.sub.3)                                                              2-pyridyl                                 CH(CH.sub.3)(CH.sub.2).sub.3                                                                 2-pyridyl                                                                            (CH.sub.2).sub.4 O                                                                          4-pyridyl                                 (CH.sub.2).sub.3 O(CH.sub.2).sub.4                                                           H      (CH.sub.2).sub.3 O(CH.sub.2).sub.4                                                          4-pyridyl                                 (CH.sub.2)O(CH.sub.2).sub.7                                                                  H      CH.sub.2 CH(CH.sub.3)O(CH.sub.2).sub.2                                                      4-pyridyl                                 C(CH.sub.3).sub.2 (CH.sub.2).sub.2 O(CH.sub.2).sub.2                                         H      O(CH.sub.2).sub.5                                                                           3-pyridyl                                 (CH.sub.2).sub.7 O                                                                           H      O(CH.sub.2).sub.7                                                                           2-pyridyl                                 (CH.sub.2).sub.11 O                                                                          H      OCH(CH.sub.3)(CH.sub.2).sub.3                                                               2-pyridyl                                 CH(CH.sub.3)(CH.sub.2).sub.6 O                                                               H      CH.sub.2 O(CH.sub.2).sub.5                                                                  C.sub.6 H.sub.5                           CH(CH.sub.3)CH.sub.2 O(CH.sub.2).sub.4                                                       C.sub.6 H.sub.5                                                                      CH(CH.sub.3)CH.sub.2 OCH.sub.2                                                              4-ClC.sub.6 H.sub.4                       (CH.sub.2).sub.3 OCH(CH.sub.3)                                                               C.sub.6 H.sub.5                                                                      CH.sub.2 O(CH.sub.2).sub.5                                                                  4-FC.sub.6 H.sub.4                        __________________________________________________________________________

EXAMPLE 21,2-alpha,3,4-alpha,4a-beta,5,6,7,8,8a-alpha-Decahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-naphthalen-2-beta-oland the 2-alpha isomer

To a -5° C. solution of 2.40 g. (5.24 mmole) of3,4-alpha,4-beta,5,6,7,8,8a-alpha-octahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-naphthalen-2(1H)-onein 15 ml. methanol and 5 ml. tetrahydrofuran is added 199 mg. (5.24mmole) of sodium borohydride. The reaction is stirred 30 minutes andthen added to 250 ml. saturated sodium chloride and 250 ml. ether. Theether extract is washed once with 250 ml. saturated sodium chloride,dried over magnesium sulfate and evaporated. The crude residue ispurified via column chromatography on 100 g. of silica gel eluted in 12ml. fractions with 2:1 pentane:ether to yield in order of elution 0.572g. (24%) of the 2-alpha isomer of the title compound and 1.53 g. (64%)of the title compound.

Title compound:

IR (CHCl₃ ): 3333, 1618 and 1575 cm⁻¹.

MS (m/e): 462 (M.sup.⊕), 447, 377, 354, 285, 269 and 91.

PMR (CDCl₃): delta 0.85 (m, terminal methyl), 1.28 (s, gem dimethyl),3.0 (bm, benzylic H), 3.75 (bm, carbinol H), 5.07 (s, benzylicmethylene), 6.9 (m, ArH) and 7.36 (s, PhH).

2-alpha Isomer of the Title Compound:

IR (CHCl₃): 3571, 3425, 1616 and 1575 cm⁻¹.

MS (m/e): 462 (M.sup.⊕), 377, 354, 285, 269 and 91.

PMR (CDCl₃): delta 0.87 (m, terminal methyl), 1.27 (s, gem dimethyl),4.18 (m, carbinol H), 5.05 (s, benzylic methylene), 6.85 (m, ArH), 7.07(d, J=8 Hz, ArH) and 7.38 (m, ArH).

The remaining compounds of Example 1 are reduced in like manner toprovide compounds having the formula shown below wherein Z and W are asdefined in Example 1. ##STR14##

The isomeric alcohols are produced in each instance.

EXAMPLE 31,2-alpha,3,4-alpha,4a-beta,5,6,7,8,8a-alpha-Decahydro-4-beta-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-naphthalen-2-beta-ol

A mixture of 1.48 g. (3.19 mmole) of1,2-alpha,3,4-alpha,4a-beta,5,6,7,8,8a-alpha-decahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-naphthalen-2-beta-oland 300 mg. of 5% Pd/C/50% H₂ O in 15 ml. of ethanol is stirred underone atmosphere of hydrogen gas for one hour. The reaction mixture isfiltered through diatomaceous earth with ethyl acetate and the filtrateevaporated to an oil. The crude oil is purified via columnchromatography on 40 g. of silica gel eluted in 10 ml. fractions with2:1 pentane:ether to yield 875 mg. (74%) of the title compound.

MP: 127°-8° C. (pentane).

IR (CHCl₃): 3333, 1618 and 1582 cm⁻¹.

MS (m/e): 372 (M.sup.⊕), 354, 287 and 269.

PMR (CDCl₃): delta 0.82 (m, terminal methyl), 1.28 (s, gem dimethyl),2.72 (m, benzylic methine), 3.82 (m, carbinol methine), 6.8 (m, ArH) and7.08 (d, J=8 Hz, ArH).

Analysis: Calc'd for C₂₅ H₄₀ O₂ : C, 80.59; H, 10.82. Found: C, 80.57;H, 10.62.

Similarly, debenzylation of the remaining beta-naphthaleneols of Example2 according to the above procedure provides the corresponding productshaving the formula shown below wherein Z and W are as defined in Example2. ##STR15##

EXAMPLE 41,2-beta,3,4-alpha,4a-beta,5,6,7,8,8a-alpha-Decahydro-4-beta-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-naphthalen-2-alpha-ol

Using the procedure of Example 3, 500 mg. (1.08 mmole) of1,2-beta,,3,4-alpha,4a-beta,5,6,7,8,8a-alpha-decahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-naphthalen-2-alpha-olis reduced to give 200 mg. (50%) of the title compound.

MP: 120°-2° C. (pentane).

IR (CHCl₃): 3333, 1626 and 1570 cm⁻¹.

MS (m/e): 372 (M.sup.⊕), 357, 354, 287 and 269.

PMR (CDCl₃): delta 0.86 (m, terminal methyl), 1.28 (s, gem dimethyl),3.00 (m, benzylic methine), 4.28 (m, carbinol methine), 6.84 (m, ArH)and 7.03 (d, J=8 Ha, ArH).

Analysis: Calc'd. for C₂₅ H₄₀ O₂ : C, 80.59; H, 10.82. Found: C, 80.47;H, 10.51.

Debenzylation of the remaining alpha naphthalenols of Example 2 by theabove procedure provides the following compounds wherein Z and W are asdefined in Example 2. ##STR16##

EXAMPLE 53,4-alpha,4a-beta,5,6,7,8,8a-alpha-Octahydro-4-beta-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-naphthalen-2(1H)-one

Using the procedure of Example 3, reduction of 1.00 g. (2.18 mmole) of3,4-alpha,4a-beta,5,6,7,8,8a-alpha-octahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-naphthalen-2(1H)-one,the title product of Example 1, gives 606 mg. (76%) of the titlecompound as an oil.

IR (CHCl₃): 3571, 3333, 1712, 1626 and 1587 cm⁻¹.

MS (m/e): 370 (M.sup.⊕), 352, 285 and 273.

PMR (CDCl₃): delta 0.82 (terminal methyl), 1.22 (s, gem dimethyl), 5.45(s, OH), 6.8 (m, ArH) and 7.03 (d, J=8 Hz, ArH).

By means of the above procedure the remaining compounds of Example 1 arereduced to give corresponding compounds of the formula wherein Z and Ware as defined in Example 1. ##STR17##

EXAMPLE 6 1,4-Dioxa-7-carboxyspiro[4.5]dec-7-ene

A mixture of 89.8 g. (0.641 mole) of 3-carboxycyclohex-3-enone and 615mg. (3.17 mmole) of p-toluenesulfonic acid monohydrate in 920 ml. ofbenzene and 362 ml. of ethylene glycol is heated at reflux with aDean-Stark trap for 3.5 hours. The cooled reaction mixture is dilutedwith 1.5 l. water and 3.2 ml. 1N sodium hydroxide. The quenched reactionmixture is then extracted with two 2 l. portions of ether. The combinedether extract is washed with 750 ml. of saturated sodium chloride, driedover magnesium sulfate and evaporated to 91.1 g. of crude oil. The crudeproduct is purified via column chromatography on 1.75 kg. of silica geleluted with 30% ether-dichloromethane to give the title compound.Crystallization of the title compound from diisopropyl ether gives 49.2g. (42%) of the title compound.

MP: 72°-3° C. (diisopropyl ether).

IR (CCl₄): 2874, 2817, 1678 and 1637 cm⁻¹.

MS (m/e): 184 (M.sup.⊕), 169, 139 and 86.

PMR (CDCl₃): delta 1.8 (bt, methylene), 2.3-2.7 (bm, methylenes), 4.0(s, ethylene), 7.0-7.2 (bm, olefinic H) and 10.8 (bs, COOH).

Analysis: Calc'd. for C₉ H₁₂ O₄ : C, 58.70; H, 6.57. Found: c, 58.39; H,6.50.

Repetition of the above procedure but replacing ethylene glycol with anequivalent amount of 1,3-butylene glycol affords the corresponding1,5-dioxa-8-carboxy-2-methylspiro[5.5]undec-8-ene.

EXAMPLE 7 1,4-Dioxa-7-carbomethoxyspiro[4.5]dec-7-ene

To a refluxing slurry of 66 g. (0.523 mole) of powdered potassiumcarbonate in 450 ml. of acetone are added simultaneously a solution of83.0 g. (0.45 mole) of 1,4-dioxa-7-carboxyspiro[4.5]dec-7-ene in 450 ml.of acetone and a solution of 56.8 g. (0.45 mole) of dimethylsulfate in450 ml. of acetone. The reaction mixture is refluxed 45 minutes longerand then filtered. The filtrate is evaporated to yield the crude titlecompound. Distillation of the crude product yields 87.7 g. (98%) of thetitle compound.

BP: 95° C. (2 torr).

IR (CCl₄): 2919, 2816, 1703 and 1642 cm⁻¹.

MS (m/e): 198 (M.sup.⊕), 183, 166, 139 and 86.

PMR (CDCl₃): delta 1.7 (bt, methylene), 2.4 (m, methylenes), 3.7 (s,methyl), 4.0 (s, ethylene) and 7.0 (bm, olefinic H).

Analysis: Calc'd. for C₁₀ H₁₄ O₄ : C, 60.17; H, 6.83. Found: C, 60.53;H, 7.11.

Repetition of this procedure but using an equivalent amount ofdiethylsulfate in place of dimethylsulfate affords the correspondingethyl ester.

EXAMPLE 8 1,4-Dioxa-7-carbomethoxy-8-(2-oxopropyl)spiro[4.5]decane

To a -78° C. solution of 74 ml. (0.575 mole) of acetonedimethylhydrazone in 1.9 l. of tetrahydrofuran is added dropwise 288 ml.(0.575 mole) of butyllithium (2M in hexane). To the resultant cloudysolution is added dropwise a solution of 54.8 g. (0.288 mole) of cuprousiodide and 167 ml. (1.15 mole) of diisopropyl sulfide in 500 ml. oftetrahydrofuran. The resultant suspension is warmed to -23° C. for 20minutes, 0° C. for 5 minutes and the resultant solution cooled to -78°C. To the above prepared cuprate solution is added dropwise 44.6 g.(0.225 mole) of 1,4-dioxa-7-carbomethoxyspiro[4.5]dec-7-ene. Theresultant mixture is stirred 15 minutes at -78° C. and then added to 4l. of saturated ammonium chloride solution (pH adjusted to 8 withammonium hydroxide). The reaction quench is extracted with 1 l. of etherand the extract washed with four 2 l. and one 1 l. portion of pH 8saturated ammonium chloride. The organic extract is dried over magnesiumsulfate and evaporated to yield 67 g. of intermediate hydrazone of thetitle compound. To the 67 g. of crude intermediate dissolved in 3 l.tetrahydrofuran and 625 ml. of pH 7 buffer is added a solution of 45.2g. (0.339 mole) of cupric chloride in 1 l. of water. The hydrolysismixture is stirred at 25° C. for 22 hours and then added to pH 8saturated ammonium chloride solution and ether. The ether extract iswashed with pH 8 saturated ammonium chloride until colorless, dried overmagnesium sulfate and evaporated to an oil.

The above procedure is repeated on a scale of 42.5 g. (0.214 mole) of1,4-dioxa-7-carbomethoxyspiro[4.5]dec-7-ene. The combined crude productfrom each preparation (113 g.) is purified via column chromatography on3 kg. of silica gel eluted with 75% ether-petroleum ether to give 80.3g. (71.2%) of the title compound as an oil.

IR (CHCl₃): 1730 and 1715 cm⁻¹.

HRMS (m/e): No M.sup.⊕, 224.1071 (C₁₇ H₁₇ O₄), 198, 157, 139 and 99.

PMR (CDCl₃): delta 1.5-2.0 (m), 2.12 (s, methyl ketone), 2.2-3.0 (m),3.62 (s, methyl ester) and 3.92 (s, ethylene).

EXAMPLE 9 1,4-Dioxa-7-carboxy-8-(2-oxypropyl)spiro[4.5]decane

To a solution of 80.2 g. (0.313 mole) of1,4-dioxa-7-carbomethoxy-8-(2-oxopropyl)spiro[4.5]decane in 500 ml.methanol and 1.6 l. tetrahydrofuran is added a solution of 36.1 g. (0.90mole) of sodium hydroxide in 300 ml. of 5:16 methanol:tetrahydrofuran.The reaction mixture is stirred 30 minutes and then diluted with 500 ml.water and saturated with sodium chloride. The reaction mixture is cooledto 0° C., 500 ml. of ether added and acidified to pH 5 with concentratedhydrochloric acid. The quenched reaction is extracted once with 2 l.ether, the pH lowered to 3.5 and extracted with 1.5 l. ether and the pHlowered to 2.0 and extracted with two 1.5 l. portions of ether. Thecombined extract is dried over magnesium sulfate and evaporated to yield72.5 g. (96% ) of the title compound as an oil.

IR (CHCl₃): 2836 (broad) and 1702 cm⁻¹.

HRMS (m/e): 242.1185 (M.sup.⊕, calc'd for C₁₇ H₁₈ O₅ : 242.1149), 224,185, 184, 139, 99 and 86.

PMR (CDCl₃): delta 1.4-2.0 (m), 2.12 (s, methyl ketone), 2.2-3.4 (m),3.95 (s, ethylene) and 9.97 (bs, COOH).

EXAMPLE 10Trans-4a,5,8,8a-tetrahydro-(1H,6H)-3-methyl-2-benzopyran-1,7-dione-7-EthyleneKetal

A mixture of 72.5 g. (0.299 mole) of1,4-dioxa-7-carboxy-8-(2-oxopropyl)spiro[4.5]decane and 14.3 g. (0.174mole) of sodium acetate in 690 ml. of acetic anhydride is heated atreflux for 12 hours and stirred at 25° C. for 5.5 hours. The reactionmixture is poured onto 585 g. ice and 440 g. of sodium acetate, dilutedwith 200 ml. ether and slowly neutralized with 454 g. of solid sodiumbicarbonate. The organic extract is dried over magnesium sulfate andevaporated. The crude residue is vacuum distilled to yield an oil whichis dissolved in 100 ml. ether and washed twice with 100 ml. saturatedsodium bicarbonate, once with 100 ml. saturated sodium chloride, driedover magnesium sulfate and evaporated to yield 63.0 g. (94%) of thetitle compound as an oil.

IR (CCl₄): 1770, 1695 and 1667 cm⁻¹.

HRMS (m/e): 224.1055 (M.sup.⊕, calc'd. for C₁₂ H₁₆ O₄ : 224.1044), 195,180, 153, 126, 99 and 86.

PMR (CDCl₃): delta 1.2-2.0 (m), 1.93 (bs, vinyl methyl), 2.0-3.0 (m),3.99 (s, ethylene) and 4.90 (bs, vinyl H).

EXAMPLE 11Trans-4a,5,8,8a-tetrahydronaphthalen-2(1H),6(7H)-dione-6-Ethylene Ketal

To a -78° C. solution of 50.4 g. (0.225 mole) oftrans-4a,5,8,8a-tetrahydro-(1H,6H)-3-methyl-2-benzopyran-1,7-dione7-ethylene ketal in 504 ml. toluene is slowly added 236 ml. (0.236 mole)of diisobutylaluminum hydride (1M in hexane). The reaction is allowed tostir 15 minutes at -78° C. and then a small portion of methanol isslowly added to remove any excess diisobutylaluminum hydride. Thequenched reaction is added to 3 l. ether and washed successively withthree 800 ml. portions of 50% saturated sodium potassium tartrate andone 800 ml. portion of saturated sodium chloride. The combined tartratewashes are extracted with 1.6 l. dichloromethane and 1.6 l. etherfollowed by washing of the combined extracts with 800 ml. saturatedsodium chloride. All organic extracts are combined, dried over magnesiumsulfate and evaporated to give a quantitative yield of intermediateketoaldehyde. To the above prepared crude ketoaldehyde dissolved in 890ml. benzene is added 16.0 g. (0.225 mole) of pyrrolidine and 9.2 g.(0.153 mole) of acetic acid. The reaction is stirred 4 hours at 25° C.and then diluted with 2 l. ether and washed with 600 ml. water, 600 ml.saturated sodium chloride, dried over magnesium sulfate and evaporatedto an oil. This crude oil is purified via column chromatography on 1 kg.of silica gel eluted with 10% hexane-ether to give 10.6 g. (23%) of thetitle compound as an oil.

IR (CHCl₃): 1677 and 1615 cm⁻¹.

HRMS (m/e): 208.1100 (M.sup.⊕, calc'd. for C₁₂ H₁₆ O₃ : 208.1095), 180,152, 99 and 86.

PMR (CDCl₃): delta 1.2-3.4 (m), 4.00 (bs, ethylene), 5.98 (dd, J=10 and3 Hz, vinyl H) and 6.71 (dd, J=10 and 2 Hz, vinyl H).

Following the procedure of Examples 7-10 and the above procedure,1,5-dioxa-8-carboxy-2-methylspiro[5.5]undec-8-ene is converted totrans-4a,5,8,8a-tetrahydro-(1H,6H)-2-benzopyran-1,7-dione 1,3-butyleneketal.

EXAMPLE 123,4-alpha,4a-beta,5,8,8a-alpha-Hexahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]naphthalen-2(1H),6(7H)-dione6-Ethylene Ketal

Using the procedure of Example 1, 23.3 g. (60 mmole) of1-bromo-2-benzyloxy-4-(1,1-dimethylheptyl)benzene and 10.0 g. (48.1mmole) of trans-4a,5,8,8a-tetrahydro-naphthalen-2(1H),6(7H)-dione6-ethylene ketal are reacted together to give 9.94 g. (40%) of the titlecompound as an oil.

IR (CHCl₃): 1712, 1613 and 1575 cm⁻¹.

HRMS (m/e): 518.3390 (M.sup.⊕, calc'd. for C₃₄ H₄₆ O₄ : 518.3392), 433,273, 243, 153, 140 and 91.

PMR (CDCl₃): delta 0.82 (m, terminal methyl), 1.23 (s, gem dimethyl),3.83 (bs, ethylene ketal), 5.05 (s, benzyl ether methylene), 6.84 (d,J=2 Hz, ArH), 6.84 (dd, J=8 and 2 Hz, ArH), 7.08 (d, J=8 Hzm ArH) and7.37 (s, PhH).

The following compounds are prepared in like manner but using theappropriate 1-bromo-2-benzyloxy-4-(substituted)benzene in place of1-bromo-2-benzyloxy-4(1,1-dimethylheptyl)benzene.

    __________________________________________________________________________     ##STR18##                                                                    Z              W      Z             W                                         __________________________________________________________________________    C(CH.sub.3).sub.2 (CH.sub.2).sub.4                                                           H      O(CH.sub.2).sub.7                                                                           H                                         (CH.sub.2).sub.8                                                                             H      OCH(CH.sub.3)(CH.sub.2).sub.9                                                               H                                         C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                           H      OCH(CH.sub.3)(CH.sub.2).sub.5                                                               H                                         (CH.sub.2).sub.7                                                                             H      OC(CH.sub.3).sub.2 (CH.sub.2).sub.5                                                         H                                         C(CH.sub.3).sub.2 (CH.sub.2).sub.8                                                           H      OC(CH.sub.3).sub.2 (CH.sub.2).sub.7                                                         H                                         CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2).sub.5                                                     H      O(CH.sub.2).sub.2 C(CH.sub.3).sub.2 (CH.sub.2).sub.2                          .             H                                         (CH.sub.2).sub.11                                                                            H      O(CH.sub.2).sub.4                                                                           C.sub.6 H.sub.5                           (CH.sub.2).sub.4                                                                             C.sub.6 H.sub.5                                                                      O(CH.sub.2).sub.6                                                                           C.sub.6 H.sub.5                           CH(CH.sub.3)(CH.sub.2).sub.5                                                                 C.sub.6 H.sub.5                                                                      OC(CH.sub.3).sub.2 (CH.sub.2).sub.3                                                         C.sub.6 H.sub.5                           CH(CH.sub.3)(CH.sub.2).sub.3                                                                 C.sub.6 H.sub.5                                                                      OCH(CH.sub.3)(CH.sub.2).sub.3                                                               C.sub.6 H.sub.5                           CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2).sub.3                                                     C.sub.6 H.sub.5                                                                      O(CH.sub.2).sub.4                                                                           4FC.sub.6 H.sub.4                         (CH.sub.2).sub.7                                                                             C.sub.6 H.sub.5                                                                      OCH(CH.sub.3)(CH.sub.2)                                                                     4FC.sub.6 H.sub.4                         CH(CH.sub.3)(CH.sub.2).sub.3                                                                 4-FC.sub.6 H.sub.4                                                                   OCH(CH.sub.2)(CH.sub.2).sub.6                                                               4FC.sub.6 H.sub.4                         CH(C.sub.2 H.sub.5)(CH.sub.2).sub.4                                                          4-FC.sub.6 H.sub.4                                                                   O(CH.sub.2).sub.8                                                                           4ClC.sub.6 H.sub.4                        CH(C.sub.2 H.sub.5)(CH.sub.2).sub.2                                                          4-ClC.sub.6 H.sub.4                                                                  OCH(C.sub.2 H.sub.5)(CH.sub.2).sub.3                                                        4ClC.sub.6 H.sub.4                        CH(CH.sub.3)(CH.sub.2).sub.3                                                                 4-ClC.sub.6 H.sub.4                                                                  (CH.sub.2).sub.4 OCH.sub.2                                                                  C.sub.6 H.sub.5                           (CH.sub.2).sub.4                                                                             4-pyridyl                                                                            (CH.sub.2).sub.6 O                                                                          C.sub.6 H.sub.5                           CH(CH.sub.3)(CH.sub.2).sub.3                                                                 4-pyridyl                                                                            CH(CH.sub.3)(CH.sub.2).sub.2 O                                                              C.sub.6 H.sub.5                           CH(C.sub.2 H.sub.5)CH.sub.2                                                                  4-pyridyl                                                                            CH(CH.sub.3)(CH.sub. 2).sub.5 O                                                             C.sub.6 H.sub.5                           (CH.sub.2).sub.7                                                                             4-pyridyl                                                                            (CH.sub.2).sub.6 O                                                                          4-FC.sub.6 H.sub.4                        CH(CH.sub.3)CH(CH.sub.3)CH.sub.2                                                             4-pyridyl                                                                            (CH.sub.2).sub.6 O                                                                          4-ClC.sub.6 H.sub.4                       CH(CH.sub.3)CH(CH.sub.3)CH.sub.2                                                             3-pyridyl                                                                            (CH.sub.2).sub.3 OCH(CH.sub.3)                                                              2-pyridyl                                 CH(CH.sub.3)(CH.sub.2).sub.3                                                                 2-pyridyl                                                                            (CH.sub.2).sub.4 O                                                                          4-pyridyl                                 (CH.sub.2).sub.3 O(CH.sub.2).sub.4                                                           H      (CH.sub.2).sub.3 O(CH.sub.2).sub.4                                                          4-pyridyl                                 (CH.sub.2)O(CH.sub.2).sub.7                                                                  H      CH.sub.2 CH(CH.sub.3)O(CH.sub.2).sub.2                                                      4-pyridyl                                 C(CH.sub.3).sub.2 (CH.sub.2).sub.2 O(CH.sub.2).sub.2                                         H      O(CH.sub.2).sub.5                                                                           3-pyridyl                                 (CH.sub.2).sub.7 O                                                                           H      O(CH.sub.2).sub.7                                                                           2-pyridyl                                 (CH.sub.2).sub.11 O                                                                          H      OCH(CH.sub.3)(CH.sub.2).sub.3                                                               2-pyridyl                                 CH(CH.sub.3)(CH.sub.2).sub.6 O                                                               H      CH.sub.2 O(CH.sub.2).sub.5                                                                  C.sub.6 H.sub.5                           CH(CH.sub.3)CH.sub.2 O(CH.sub.2).sub.4                                                       C.sub.6 H.sub.5                                                                      CH(CH.sub.3)CH.sub.2 OCH.sub.2                                                              4-ClC.sub.6 H.sub.4                       (CH.sub.2).sub.3 OCH(CH.sub.3)                                                               C.sub.6 H.sub.5                                                                      CH.sub.2 O(CH.sub.2).sub.5                                                                  4-FC.sub. 6 H.sub.4                       (CH.sub.2).sub.5 O                                                                           H      (CH.sub.2).sub.3 O                                                                          C.sub.6 H.sub.5                           (CH.sub.2).sub.9 O(CH.sub.2).sub.4                                                           H      (CH.sub.2).sub.3 O(CH.sub.2).sub.5                                                          C.sub.6 H.sub.5                           __________________________________________________________________________

EXAMPLE 131,2-alpha,3,4-alpha,4a-beta,5,8,8a-alpha-Octahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-beta-hydroxy-naphthalen-6(7H)-one6-Ethylene Ketal and Its 2-alpha Isomer

Using the procedure of Example 2 9.8 g. (18.9 mmole) of3,4-alpha,4a-beta,5,8,8a-alpha-hexahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-naphthalen-2(1H),6(7H)-dione6-ethylene ketal, the title product of Example 12, is reduced to 1.5 g.(15%) of the 6-alpha isomer of the title compound, 1.75 g. (18%) ofmixture and 4.0 g. (41%) of the title compound. Title Compound:

IR (CHCl₃): 5597, 3448, 1618 and 1582 cm⁻¹.

HRMS (m/e): 520.3580 (M.sup.⊕, calc'd. for C₃₄ H₄₈ O₄ : 520.3548), 435,244, 243, 154, 153, 140 and 91.

PMR (CDCl₃): delta 0.81 (m, terminal methyl), 1.22 (s, gem dimethyl),3.2 (m, benzylic methine), 3.8 (m, carbinol methine and ethylene ketal),5.02 (s, benzylic methylene), 9.0 (m, ArH), 7.07 (d, J=8 Hz, ArH) and7.35 (s, PhH).

2-alpha Isomer of the Title Compound:

IR (CHCl₃): 3448, 1613 and 1578 cm⁻¹.

HRMS (m/e): 520.3496 (M.sup.⊕, calc'd. for C₃₄ H₄₈ O₄ : 520.3548), 435,323, 244, 243 and 91.

PMR (CDCl₃): 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.4 (m,benzylic methine), 3.80 (bs, ethylene ketal), 4.12 (m, carbinolmethine), 5.02 (s, benzylic methylene), 6.88 (m, ArH), 7.07 (d, J=8 Hz,ArH) and 7.38 (m, PhH).

Reduction of the remaining compounds of Example 12 in like manneraffords their corresponding isomeric 2-hydroxynaphthalen-6(7H)-ones ofthe formula ##STR19## wherein Z and W are as defined in Example 12.

EXAMPLE 141,2-alpha,3,4-alpha,4a-beta,5,8,8a-alpha-Octahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-beta-hydroxy-naphthalen-6(7)-one

A mixture of 2.0 g. (3.85 mmole) of1,2-alpha,3,4-alpha,4a-beta,5,8,8a-alpha-octahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-beta-hydroxy-naphthalen-6(7H)-one6-ethylene ketal, the title compound of Example 13, in 50 ml.tetrahydrofuran and 25 ml. 1N hydrochloric acid is heated at 70° C. for4 hours. The reaction is cooled and added to 250 ml. saturated sodiumchloride-300 ml. ether. The ether extract is washed twice with 250 ml.portions of saturated sodium bicarbonate, dried over magnesium sulfateand evaporated to yield 1.9 g. (100%) of the title compound as an oil.

IR (CHCl₃): 3425, 1709, 1608 and 1575 cm⁻¹.

HRMS (m/e): 476.3278 (M.sup.⊕, calc'd. for C₃₂ H₄₄ O₃ : 476.3285), 371,259, 233, 200, 147 and 91.

PMR (CDCl₃): delta 0.84 (m, terminal methyl), 1.22 (s, gem dimethyl, 3.2(m, benzylic methine), 3.85 (m, carbinol methine), 5.05 (s, benzylicmethylene), 6.9 (m, ArH), 7.03 (d, J=8 Hz, ArH) and 7.38 (s, PhH).

Acid treatment of the remaining compounds of Example 13 affords thecorresponding 2-hydroxynaphthalen-6(7H)-ones.

EXAMPLE 151,2-alpha,3,4-alpha,4a-beta,5,8,8a-alpha-Octahydro-4-beta-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-beta-hydroxy-naphthalen-6(7H)-one

Following the procedure of Example 3 330 mg. (0.692 mmole) of1,2-alpha,3,4-alpha,4a-beta,5,8,8a-alpha-octahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-beta-hydroxy-naphthalen-6(7H)-oneis reduced to give 218 mg. of the title compound.

MP: 160°-161° C. (acetonitrile).

IR (CHCl₃): 3571, 3333, 1706, 1621 and 1582 cm⁻¹.

HRMS (m/e): 386.2844 (M.sup.⊕, calc'd. for C₂₅ H₃₈ O₃ : 386.2817), 368,301, 283 and 110.

PMR (100 MHz, CDCl₃): delta 0.84 (bt, J=6 Hz, terminal methyl), 1.24 (s,gem dimethyl), 3.08 (m, benzylic methine), 3.32 (bd, J=4 Hz, OH), 3.82(m, carbinol methine), 6.7 (m, ArH), 6.96 (d, J=8 Hz, ArH) and 8.1 (bs,OH).

Following the procedure of Example 14 and the above procedure thetabulated compounds of Example 13 are converted to compounds having theformula shown below wherein Z and W are as defined in Example 13:##STR20##

EXAMPLE 161,2-alpha,3,4-alpha,4a-beta,5,6-beta,7,8,8a-alpha-Decahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-naphthalen-2-beta,6-alpha-diol

Following the procedure of Example 2, reduction of 500 mg. (1.05 mmole)of1,2-alpha,3,4-alpha,4a-beta,5,8,8a-alpha-octahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl]-2-beta-hydroxy-naphthalen-6(7H)-one,the title product of Example 14, gives a quantitative yield of the titlecompound as an oil.

PMR (CDCl₃): delta 0.84 (m, terminal methyl), 1.25 (s, gem dimethyl),˜3.0 (m, benzylic methine), 3.8 (bm, carbinol methine), 5.02 (s,benzylic methylene), 6.95 (m, ArH), 7.10 (d, J=8 Hz, ArH) and 7.40 (s,PhH).

EXAMPLE 171,2-alpha,3,4-alpha,4a-beta,5,6-alpha,7,8,8a-alpha-Decahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-naphthalen-2-beta,6-beta-diol

To a 25° C. solution of 400 mg. (0.84 mmole) of the title product ofExample 14,1,2-alpha,3,4-alpha,4a-beta,5,8,8a-alpha-octahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-beta-hydroxy-naphthalen-6(7H)-onein 2 ml. of tetrahydrofuran is added 5.04 ml. (2.52 mmole) of potassiumtri-sec-butylborohydride (0.5M) in tetrahydrofuran). The reaction isstirred 30 minutes, cooled to 0° C. and then oxidized with 10 ml.tetrahydrofuran, 30 ml. 1N sodium hydroxide and 6 ml. 30% hydrogenperoxide. After 30 minutes the reaction is added to 250 ml. saturatedsodium chloride and 300 ml. ether. The ether extract is washed once with250 ml. saturated sodium chloride, dried over magnesium sulfate andevaporated to an oil. This crude oil is purified via columnchromatography on 100 g. of silica gel eluted in 10 ml. fractions with 1l. of 50% ether-hexane and then 100% ether to yield 283 mg. (71%) of thetitle compound as an oil.

R_(f) =0.23 (0.25 mm silica gel; ether).

Reduction of the remaining compounds of Example 14 according to theabove procedure affords the corresponding2-beta,6-beta-naphthalenediols.

EXAMPLE 181,2-alpha,3,4-alpha,4a-beta,5,6-beta,7,8,8a-alpha-Decahydro-4-beta-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-naphthalen-2-beta,6-alpha-diol

Following the procedure of Example 3, catalytic reduction of 502 mg.(1.05 mmole) of crude1,2-alpha,3,4-alpha,4a-beta,5,6-beta,7,8,8a-alpha-decahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]naphthalen-2-beta,6-alpha-diolgives 300 mg. (74%) of the title compound as a foam.

PMR (100 MHz, CDCl₃): delta 0.83 (m, terminal methyl), 2.84 (m, benzylicmethine), 3.47 and 3.87 (m, carbinol methines), 6.80 (m, ArH) and 6.99(d, J=8 Hz, ArH).

HRMS (m/e): 388.2781 (M.sup.⊕, calc'd. for C₂₅ H₄₀ O₃ : 388.2973), 370,352, 303, 285 and 267.

EXAMPLE 191,2-alpha,3,4-alpha,4a-beta,5,6-alpha,7,8,8a-alpha-Decahydro-4-beta-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-naphthalen-2-beta,6-beta-diol

Following the procedure of Example 3, 283 mg. (0.592 mmole)1,2-alpha,3,4-alpha,4-a-beta,5,6-alpha,7,8,8a-alpha-decahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-naphthalen-2-beta,6-beta-diolis reduced to provide 145 mg. (63%) of the title compound.

MP: 91°-2° C. (diisopropyl ether).

PMR (100 MHz, CDCl₃): delta 0.85 (m, terminal methyl), 1.20 (s, gemdimethyl), 280 (m, benzylic methine), 3.80 (bm, carbinol methine), 4.03(m, carbinol methine), 6.85 (m, ArH) and 7.12 (d, J=8 Hz, ArH).

HRMS (m/e): 388.2985 (M.sup.⊕, calc'd. for C₂₅ H₄₀ O₃ : 388.2973), 370,352, 303, 285 and 267.

In like manner, the compounds of Examples 16 and 17 are reduced toprovide compounds of the formula below wherein Z and W are as defined insaid Examples. ##STR21##

EXAMPLE 201,2-alpha,3,4-alpha,4a-beta,5,8,8a-alpha-Octahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-6(7H)-methylene-naphthalen-2-beta-ol

To a 15° C. mixture of triphenylphosphorous methylide [from 2.25 g.(6.30 mmoles) of methyltriphenylphosphonium bromide and 151 mg. (6.30mmole) of sodium hydride] in 7 ml. of dimethyl sulfoxide is added asolution of 1.0 g. (2.10 mmole) of1,2-alpha,3,4-alpha,4a-beta,5,8,8a-alpha-octahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-beta-hydroxy-naphthalen-6(7H)-one,the title compound of Example 14, in 3 ml. of dimethyl sulfoxide and 5ml. of tetrahydrofuran. The reaction mixture is stirred 20 minutes andthen added to 250 ml. of water, 200 ml. ether and 100 ml. pentane. Theorganic extract is washed with two 125 ml. portions of water, dried overmagnesium sulfate and evaporated. Triphenylphosphine oxide is removedfrom the crude product by crystallization in ether-pentane. The titlecompound is obtained upon evaporation of the filtrate in quantitativeyield as an oil.

R_(f) =0.22 (0.25 mm silica gel; 50% ether-hexane).

PMR (CDCl₃): delta 0.82 (m, terminal methyl), 1.23 (s, gem dimethyl),3.02 (m, benzylic methine), 3.7 (m, carbinol methine), 4.43 (m, vinylmethylene), 5.02 (s, benzylic methylene), 6.85 (m, ArH), 7.04 (d, J=8Hz, ArH) and 7.33 (s, Ph).

By means of the above procedure the remaining compounds of Example 14are converted to their 6-methylene derivatives.

EXAMPLE 211,2-alpha,3,4-alpha,4a-beta,5,6-beta,7,8,8a-alpha-Decahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-6-alpha-hydroxymethylnaphthalen-2-beta-oland Its 6-beta-Isomer

To a 0° C. solution of 925 mg. (2.10 mmole)1,2-alpha,3,4-alpha,4a-beta,5,8,8a-alpha-octahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-6(7H)-methylene-naphthalen-2-beta-ol,the title compound of Example 20, in 10 ml. of tetrahydrofuran is added4.2 ml. (4.20 mmole) of borane tetrahydrofuran complex (1M intetrahydrofuran). The reaction is stirred 45 minutes and then oxidizedby the addition of 6.3 ml. (12.6 mmole) of 2N sodium hydroxide and 1.08ml. (12.6 mmole) of 30% hydrogen peroxide. After stirring 30 minutes thereaction mixture is added to 500 ml. saturated sodium chloride and 300ml. ether. The organic extract is washed once with 250 ml. of saturatedsodium chloride, dried over magnesium sulfate and evaporated to an oil.Purification of the crude product via column chromatography on 100 g. ofsilica gel eluted with 2:1 ether:hexane gives in order of elution 275mg. (27%) of the title compound and 670 mg. (65%) of the 6-beta-isomerof the title compound.

Title Compound:

HRMS (m/e): 492.3605 (M.sup.⊕, calc'd. for C₃₃ H₄₈ O₃ : 492.3597), 407,389, 384, 299 and 91.

6-beta-Isomer of the Title Compound:

HRMS (m/e): 492.3555 (M.sup.⊕, calc'd. for C₃₃ H₄₈ O₃ : 492.3597), 407,389, 384, 299 and 91.

EXAMPLE 221,2-alpha,3,4-alpha,4a-beta,5,6-beta,7,8,8a-Decahydro-4-beta-[4-(1,1-dimethylheptyl-2-hydroxyphenyl]-6-alpha-hydroxymethyl-naphthalen-2-beta-ol

Catalytic reduction of 270 mg. (0.548 mmole) of1,2-alpha,3,4-alpha,4a-beta,5,6-beta,7,8,8a-alpha-decahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-6-alpha-hydroxymethyl-naphthalen-2-beta-olaccording to the procedure of Example 3 gives 178 mg. (81%) of the titlecompound as a foam.

HRMS (m/e): 402.3109 (M.sup.⊕, calc'd. for C₂₆ H₄₂ O₃ : 402.3129), 384,317, 299 and 147.

PMR (270 MHz, CDCl₃): delta 0.94 (t, J=7 Hz, terminal methyl), 1.39 (s,gem dimethyl), 3.11 (m, benzylic methine), 3.70 (m, hydroxymethylene),4.19 (m, carbinol methine), 6.27 (s, OH), 7.43 (bs, ArH), 7.59 (bd, J=8Hz, ArH) and 7.80 (d, J=8 Hz, ArH).

EXAMPLE 231,2-alpha,3,4-alpha,4a-beta,5,6-alpha,7,8,8a-alpha-Decahydro-4-beta-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-6-beta-hydroxymethyl-naphthalen-2-beta-ol

Reduction of 660 mg. (1.34 mmole) of1,2-alpha,3,4-alpha,4a-beta,5,6-alpha,7,8,8a-alpha-decahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-6-beta-hydroxymethyl-naphthalen-2-beta-olaccording to the method of Example 3 gives 421 mg. (78%) of the titlecompound as an oil.

HRMS (m/e): 402.3109 (M.sup.⊕, calc'd. for C₂₆ H₄₂ O₃ : 402.3129), 384,317, 299, 161 and 147.

PMR (270 MHz, CDCl₃): delta 0.96 (t, J=7 Hz, terminal methyl), 1.35 (s,gem dimethyl), 3.07 (m, benzylic methine), 4.00 (m, hydroxymethylene),4.22 (m, carbinol methine), 6.20 (s, OH), 7.43 (bs, ArH), 7.59 (bd, J=8Hz, ArH) and 7.76 (d, J=8 Hz, ArH).

By means of the procedure of Example 21 and of the above procedure, the6-methylene derivatives of Example 20 are converted to corresponding6-hydroxymethyl derivatives having the formula wherein Z and W are asdefined in Example 20. ##STR22##

EXAMPLE 241,2-alpha,3,4-alpha,4a-beta,5,6-alpha,7,8,8a-alpha-Decahydro-4-beta[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-beta-(d-Mandeloyloxy)-6-beta-(d-Mandeloyloxy)methylNaphthalene

A mixture of 940 mg. (1.91 mmole) of1,2-alpha,3,4-alpha,4a-beta,5,6-alpha,7,8,8a-alpha-decahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-6-beta-hydroxymethylnaphthalene-2-beta-ol,912 mg. (6.00 mmole) of d-mandelic acid and 38 mg. (0.2 mmole) ofp-toluenesulfonic acid monohydrate in 15 ml. of benzene is heated atreflux for 11 hours. Water is removed via a soxhlet extractor filledwith 3A molecular sieves. The reaction is cooled and diluted in 250 ml.ether--250 ml. saturated sodium bicarbonate. The organic extract isdried over magnesium sulfate and evaporated to yield an oil. The crudeoil is purified via column chromatography on 200 g. of silica gel elutedwith 50% ether-hexane to yield, in order of elution, 481 mg.(crystallized from diisopropyl ether) (33%) of diastereomer A and 352mg. (24%) of diastereomer B as an oil.

Diastereomer A of Title Compound:

MP: 148°-9° C. (from diisopropyl ether).

[alpha]_(D) ²⁰° =+17.84° (c=0.419, 20:1 CH₃ OH:CHCl₃).

PMR (CDCl₃, 100 MHz): delta 0.82 (m, terminal methyl), 1.24 (s, gemdimethyl), 2.95 (m, benzylic methine), 3.42 and 3.44 (d, J=6 Hz, OH),4.08 (m, methylene), 4.85 (m, methine), 4.94 and 5.10 (d, J=6 Hz,methines), 5.08 (s, benzylic methylene), 6.92 (m, ArH), 7.27 (s, PhH)and 7.40 (m, PhH).

Analysis: Calc'd. for C₄₉ H₆₀ O₇ : C, 77.33; H, 7.95. Found: C, 77.40;H, 8.14.

Diastereomer B of Title Compound:

[alpha]_(D) ²⁰° =+51.34° (c=1.073, 20:1 CH₃ OH:CHCl₃).

PMR (CDCl₃, 100 MHz): 0.80 (m, terminal methyl), 1.20 (s, gem dimethyl),2.90 (m, benzylic methine), 3.28 and 3.43 (d, J=6 Hz, OH), 4.07 (m,methylene), 4.83 (m, methine), 4.99 (s, benzylic methylene), 5.05 and5.09 (d, J=6 Hz, methines), 6.84 (m, ArH), 7.28 (s, PhH), and 7.31 (m,PhH).

EXAMPLE 251,2-alpha,3,4-alpha,4a-beta,5,6-alpha,7,8,8a-alpha-Decahydro-4-beta-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]6-beta-Hydroxymethylnaphthalen-2-beta-ol(Enantiomer A)

A mixture of 590 mg. (0.776 mmole) of1,2-alpha,3,4-alpha,4a-beta,5,6-alpha,7,8,8a-alpha-decahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-beta-(d-mandeloyloxy)-6-beta-(d-mandeloyloxy)methylnaphthalene,diastereomer A, and 429 mg. (3.11 mmole) of potassium carbonate in 7 ml.methanol--2 ml. tetrahydrofuran--1 ml. water is stirred 20 hours at 25°C. The reaction is added to 250 ml. ether--250 ml. saturated sodiumbicarbonate. The organic extract is dried over magnesium sulfate andevaporated to give a quantitative yield of the title compound.

HRMS (m/e): 492.3614 (M⁺, calc'd. for C₃₃ H₄₅ O₃ : 492.2277), 407, 299and 91.

In like manner, 596 mg. (0.784 mmole) of the B diastereomer of the abovereactant affords a quantitative yield of the B enantiomer of the titlecompound as an oil.

EXAMPLE 261,2-alpha,3,4-alpha,4a-beta,5,6-alpha,7,8,8a-alpha-Decahydro-4-beta-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]-6-beta-hydroxymethyl-2-beta-naphthalenol,Enantiomer A

Using the procedure of Example 3, 2.54 g. (5.17 mmole) of1,2-alpha-3,4-alpha,4a-beta,5,6-alpha,7,8,8a-alpha-decahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-6-beta-hydroxymethyl-2-beta-naphthalenol,diastereomer A, gives 2.0 g. (97%) of the title compound.

MP: 115°-116° C. (from ethyl acetate-hexane).

Analysis: Calc'd. for C₂₆ H₄₂ O₃ : C, 77.56; H, 10.52. Found: C, 77.66;H, 10.19.

[alpha]_(D) ²⁰° C. =-28.68° (c=1.55, CH₃ OH).

PMR (CDCl₃, 100 MHz): delta 0.81 (m, terminal methyl), 1.19 (s, gemdimethyl), 2.70 (m, benzylic methine), 3.36-3.98 (m), 5.58 (bs, OH) and6.56-7.06 (m, ArH).

HRMS (m/e): 402.3167 (M.sup.⊕, calc'd. for C₂₆ H₄₂ O₃ : 402.3123) 384,317, 249, 161 and 147.

Similarly, 356 mg. (0.784 mmole) of enantiomer B affords 306 mg. (97%yield) of the B enantiomer of the title compound as a glass.

[alpha]_(D) ²⁰° C. =+27.98° (c=1.047, CH₃ OH).

PMR (CDCl₃, 100 MHz): delta 0.81 (m, terminal methyl), 1.19 (s, gemdimethyl), 2.70 (m, benzylic methine), 3.36-3.98 (m), 5.58 (bs, OH) and6.56-7.06 (m, ArH).

HRMS (m/e): 402.3154 (M.sup.⊕, calc'd. for C₂₆ H₄₂ O₃ : 402.3123) 384,317, 300 and 299.

EXAMPLE 271,2-alpha,3,4-alpha,4a-beta,5,6,7,8,8a-alpha-Decahydro-4-beta-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-6-methylnaphthalen-2-beta-ol

Catalytic hydrogenation of 1.0 g. (2.11 mmole) of1,2-alpha,3,4-alpha,4a-beta,5,8,8a-alpha-octahydro-4-beta-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-6(7H)-methylenenaphthalen-2-ol,the title compound of Example 20, according to the procedure of Example3 affords the title compound as a mixture of the isomeric 6-methylderivatives.

The remaining 6-methylene compounds of Example 20 are reduced in likemanner to the corresponding 6-methyl derivatives.

EXAMPLE 28 General Hydrochloride Salt Formation

Excess hydrogen chloride is passed into a methanol solution of theappropriate compound of formula I having a basic group and ether addedto the resulting mixture to insure maximum precipitation of the salt.

In this manner, compounds of formula I described herein which have abasic group are converted to their hydrochloride, hydrobromide, sulfate,nitrate, phosphate, acetate, butyrate, citrate, malonate, maleate,fumarate, malate, glycolate, gluconate, lactate, salicylate,sulfosalicylate, succinate, pamoate, tartrate and embonate salts.

EXAMPLE 291,2-alpha,3,4-alpha,4a-beta,5,6,7,8,8a-alpha-Decahydro-2-beta-Acetoxy-4-beta-[2-acetoxy-4-(1,1-dimethylheptyl)phenyl]-naphthalene

A solution of 2.0 g. of1,2,3,4-alpha,4a-beta,5,6,7,8,8a-alpha-decahydro-[4-(1,1-dimethylheptyl)-2-hydroxy)phenyl]-naphthalen-2-beta-olin 20 ml. of pyridine is treated at 10° C. with 20 ml. acetic anhydrideand the mixture stirred for 18 hours under nitrogen. It is then pouredonto ice/water and acidified with dilute hydrochloric acid. Theacidified mixture is extracted with ethyl acetate (2×100 ml.), theextracts combined, washed with brine and dried (MgSO₄). Evaporationunder reduced pressure gives the title product as an oil.

Similarly, substitution of anhydrides of propionic, butyric and valericacid for acetic anhydride affords the corresponding ester derivatives.

Reduction of the 2-oxo group by means of sodium borohydride according tothe procedure of Example 2 affords the corresponding 2-hydroxyderivatives, both isomers being formed.

EXAMPLE 303,4-alpha,4a-beta,5,6,7,8,8a-alpha-Octahydro-4-beta-[2-acetoxy-4-(1,1-dimethylheptyl)phenyl]-naphthalen-2(1H)-one

Repetition of the procedure of Example 29 but using 10 ml. each ofpyridine and acetic anhydride and3,4-alpha,4a-beta,5,6,7,8,8a-alpha-octahydro-4-beta-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]naphthalen-2(1H)-one(2.0 g.) as reactant affords the title compound as an oil.

Replacement of acetic anhydride by propionic, butyric or valeric acidanhydrides affords the corresponding alkanoyl derivatives.

Sodium borohydride reduction of the 2-oxo group according to theprocedure of Example 2 affords an isomeric mixture of the corresponding2-hydroxy derivatives.

EXAMPLE 311,2-alpha,3,4-alpha,4a-beta,5,6-alpha,7,8,8a-alpha-Decahydro-2-beta-acetoxy-4-beta-[2-acetoxy-4-(1,1-dimethylheptyl)phenyl]-6-beta-acetoxymethyl-naphthalene

Following the procedure of Example 29, 2.0 g. of1,2-alpha,3,4-alpha,4a-beta,5,6-alpha,7,8,8a-alpha-decahydro-4-beta-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-6-beta-hydroxymethylnaphthalen-2-beta-olis acetylated using 30 ml. each of acetic anhydride and 30 ml. ofpyridine to give the title product.

Substitution of acetic anhydride by valeric acid anhydride provides thecorresponding trivaleryl derivative.

EXAMPLE 321,2-alpha,3,4-alpha,4a-beta,5,6-alpha,7,8,8a-alpha-Decahydro-4-beta-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-6-beta-(4-morpholinobutyryloxymethyl)naphthalen-2-beta-olhydrochloride

Dicyclohexylcarbodiimide (1.0 mmole) and 4-N-piperidylbutyric acidhydrochloride (1.0 mmole) are added to a solution of1,2-alpha,3,4-alpha,4a-beta,5,6-alpha,7,8,8a-alpha-decahydro-4-beta-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-6-beta-hydroxymethylnapthalen-2-beta-ol(1.0 mmole) in methylene chloride at room temperature. The mixture isstirred for 18 hours, then cooled to 0° C. and filtered. Evaporationgives the title product. Also produced are the corresponding esterwherein acylation has occurred at the phenolic hydroxy group and thediester wherein the phenolic hydroxy group and the 6-hydroxymethyl groupare esterified.

PREPARATION A Methyl 3-benzyloxybenzoate

A mixture of 1564 g. (10.2 mole) of methyl 3-hydroxybenzoate, 1407.6 g.(10.2 mole) potassium carbonate and 1285.2 g. (10.2 mole) benzylchloride in 5 l. of acetone is heated at reflux for 22 hours. Thereaction mixture is then cooled, filtered and the filtrate evaporated.The residue is crystallized in a small volume of pentane to give aquantitative yield of the title compound.

MP: 74°-77° C. (Pentane).

IR (CHCl₃): 1724, 1587, 1486, and 1449 cm⁻¹.

MS (m/e): 242 (M⁺), 211 and 91.

PMR (CDCl₃): delta 3.95 (s, methyl), 5.10 (s, methylene), 7.2 (m, ArH),7.35 (m, PhH) and 7.65 (m, ArH).

Analysis: Calc'd. for C₁₅ H₁₄ O₃ : C, 74.38; H, 5.78. Found: C, 74.58;H, 6.09.

PREPARATION B 3-Benzyloxybenzene-2-propanol

To a 0° solution of 2.2 mole of methyl magnesium iodide in 1.5 l. etheris added a solution of 200 g. (1.06 mole) of methyl 3-benzyloxybenzoatein 500 ml. ether and 500 ml. tetrahydrofuran. The reaction mixture isstirred for 3 hours and then added to 1.5 l. ice cold saturated ammoniumchloride and 2 l. ether. The organic extract is dried over magnesiumsulfate and evaporated to an oil. Crystallization of the crude oil inpetroleum ether gives 186 g. (93%) of the title compound.

MP: 45°-48° C. (Petroleum ether).

IR (CHCl₃): 3509, 3333, 1587, 1570, 1475 and 1443 cm⁻¹.

MS (m/e): 242 (M⁺), 225 and 91.

PMR (CDCl₃): delta 1.85 (s, gem dimethyl), 2.05 (s, OH), 5.1 (s,benzylic methylene), 7.2 (m, ArH) and 7.45 (bs, PhH).

PREPARATION C 2-(3-Benzyloxyphenyl)-2-chloropropane

A mixture of 200 g. (0.826 mole) of 3-benzyloxybenzene-2-propanol in 50ml. of hexane and 1 l. of concentrated hydrochloric acid is shaken for15 minutes in a 2 l. separatory funnel. The organic layer is removed andwashed with saturated sodium bicarbonate. The neutralized organicextract is dried over magnesium sulfate and evaporated to give aquantitative yield of the title compound as an oil.

PMR (CDCl₃): delta 1.98 (s, gem dimethyl), 5.03 (s, benzylic methylene),6.8-7.7 (m, ArH) and 7.38 (bs, PhH).

2-(3-Benzyloxyphenyl)-2-bromopropane

In a similar manner 5.0 g. (20.6 mmole) of 3-benzyloxybenzene 2-propanoland 200 ml. of 35% hydrobromic acid gives a quantitative yield of thetitle compound as an oil.

PMR (CDCl₃): delta 2.14 (s, gem dimethyl), 5.00 (s, benzylic methylene),6.6-7.5 (m, ArH) and 7.33 (bs, PhH).

PREPARATION D 1-Benzyloxy-3-(1,1-dimethylheptyl)benzene

To a 0° C. mixture of 10.1 mmole of n-hexyl magnesium bromide in 5 ml.of hexane is added dropwise a solution of 2.0 g. (7.69 mmole) of2-(3-benzyloxyphenyl)-2-chloropropane in 14 ml. of hexane. The reactionmixture is stirred 5 minutes longer and then added to 500 ml. ofsaturated ammonium chloride and 300 ml. ether. The organic extract isdried over magnesium sulfate and evaporated to an oil. The oil ispurified via column chromatography on 150 g. of silica gel eluted withhexane to yield 841 mg. (35%) of the title compound as an oil.

IR (CHCl₃): 1600, 1575, 1481, 1471 and 1447 cm⁻¹.

MS (m/e): 310 (M⁺), 225 and 91.

PMR (CDCl₃): delta 0.84 (terminal methyl), 1.28 (s, gem dimethyl), 5.04(s, benzylic methylene), 6.7-7.6 (m, ArH) and 7.42 (bs, PhH).

PREPARATION E 2-Benzyloxy-1-bromo-4-(1,1-dimethylheptyl)benzene

To a -78° C. solution of 42.6 g. (0.134 mole) of1-benzyloxy-3-(1,1-dimethylheptyl)benzene and 12.2 g. (0.200 mole) tot-butylamine in 300 ml. of dichloromethane is added a solution of 27.2g. (0.151 mole), bromine in 100 ml. of dichloromethane. The reactionmixture is then allowed to warm to 25° C. and added to 500 ml. saturatedsodium sulfite and 500 ml. ether. The organic extract is washed with two500 ml. portions of saturated sodium bicarbonate, dried over magnesiumsulfate and evaporated to an oil. The crude product is purified viacolumn chromatography on 500 g. of silica gel eluted with 10%ether-hexane to give 41.9 g. (80%) of the title compound as an oil.

IR (CHCl₃): 1587, 1570 and 1481 cm⁻¹.

MS (m/e): 390, 388 (M⁺), 309, 299 and 91.

PMR (CDCl₃): delta 0.80 (m, terminal methyl), 1.20 (s, gem dimethyl),5.05 (s, benzylic methylene), 6.8 (m, ArH) and 7.35 (m, ArH and PhH).

PREPARATION F Trans-4a,5,8,8a-Tetrahydronaphthalen-2(1H),6(7H)-dione6-Ethylene Ketal

(a) 3-alpha-Phenylthio-decahydro-2,6-naphthalenedione 6-monoethyleneketal.

To a -78° C. solution of 3.08 ml. (22 mmole) of diisopropylamine in 22ml. of tetrahydrofuran is added 8.4 ml. (21 mmole) of 2.5Mn-butyllithium in hexane. The resultant solution is stirred 30 minutesat -78° C. A solution of 2.10 g. (10 mmole) ofdecahydro-2,6-naphthalenedione monoethylene ketal in 5 ml. oftetrahydrofuran is slowly added and the resultant solution stirred 30minutes at -78° C. and 30 minutes at room temperature. The reactionsolution is cooled to 0° C. and a solution of 4.79 g. (22 mmole) ofdiphenyldisulfide is rapidly added. The reaction solution is warmed toroom temperature, stirred one hour and then quenched by addition to 250ml. ether--250 ml. saturated sodium chloride. The organic extract isdried over magnesium sulfate and evaporated to an oil. The crude oil ispurified via column chromatography on 100 g. of silica gel eluted with50% ether-hexane to yield 947 mg. (crystallized from diisopropyl ether)(30%) of the 3-alpha isomer of the title compound.

MP: 127°-130° C. (from diisopropyl ether).

PMR (CDCl₃): delta 0.95-2.4 (m), 2.95 (m, axial methine 1,3 to axialsulfur), 3.70 (m, methine alpha to sulfur), 4.00 (s, ethylene ketal) and7.30 (m, PhH).

MS (m/e): 318 (M⁺), 209, 181, 125, 109, 99 and 86.

IR (CHCl₃): 1706, 1600 and 1582 cm⁻¹.

(b) 3-alpha-Phenylsulfenyl-decahydro-2,6-naphthalene-dione6-monoethylene ketal.

To a 0° C. solution of 912 mg. (2.87 mmole) of3-alpha-phenylthiodecahydro-2,6-naphthalenedione 6-monoethylene ketal in50 ml. of dichloromethane is slowly added a solution of 494 mg. (2.87mmole) of m-chloroperoxybenzoic acid in 20 ml. of dichloromethane. Theresultant mixture is stirred two hours at 0° C. to 20° C. and then addedto 250 ml. ether--250 ml. 10% sodium sulfite. The organic extract iswashed twice with 250 ml. portions of saturated sodium bicarbonate,dried over magnesium sulfate and evaporated to an oil. The crude oil ispurified via column chromatography on 50 g. of silica gel eluted withether to yield 850 mg. (87%) of the title compound as an oily mixture ofdiastereomers.

PMR (CDCl₃): 0.9-2.8 (m), 3.46 (m, methine alpha to sulfur), 3.92 and4.00 (s, ethylene ketal) and 7.55 (m, PhH).

To a 0° C. slurry of 21.9 g. (0.547 mole) of potassium hydride in 200ml. of dimethoxyethane was added 43.2 g. (0.277 mole) of methylphenylsulfinate. To the resultant mixture was added, dropwise over a 30minute period, a solution of 49.6 g. (0.236 mole) ofdecahydro-2,6-naphthalenedione monoethylene ketal in 150 ml. ofdimethoxyethane. The reaction was stirred one hour at 0° C. and thenquenched by the slow addition of 9 ml. (0.5 mole) of water. The quenchedreaction mixture was added to 150 ml. ether-150 ml. dichloromethane-125ml. 6N HCl-375 ml. saturated sodium chloride. The aqueous phase wasextracted with another 150 ml. portion of dichloromethane. The combinedorganic extract was dried over magnesium sulfate and evaporated to asemisolid. It can, if desired, be purified by column chromatography asdescribed above. It can, however, be used as is in the next step (c).

(c) Trans-4a,5,8,8a-tetrahydronaphthalene-2(1H),6(7H)-dione 6-ethyleneketal.

The crude product obtained by the alternative method under (b) was mixedwith 26.8 g. (0.268 mole) of calcium carbonate in one liter of tolueneand heated at 110° C. for 30 minutes. The reaction mixture was cooled,filtered through magnesium sulfate and the filtrate evaporated on arotovapor to yield an oil which was purified via column chromatographyon 500 g. of silica gel eluted with 39% ether-hexane to yield 40 g.(81%) of the title compound.

MP: 58°-59° C. (from diisopropyl ether).

IR (CHCl₃): 1681, 1658 (shoulder) and 1613 cm⁻¹.

PMR (100 MHz, CDCl₃): delta 1.32-2.62 (m), 4.00 (s, ethylene ketal),5.97 (dd, J=10 and 3 Hz, olefin) and 6.71 (dd, J=10 and 2 Hz, olefin).

HRMS (m/e): 208.1099 (M⁺), 180, 179, 172, 170, 153 and 99 (100%).

Analysis: Calc'd. for C₁₂ H₁₆ O₃ : C, 69.21; H, 7.74. Found: C, 69.11;H, 7.49.

We claim:
 1. A compound having the formula ##STR23## wherein R ishydroxy or alkanoyloxy having from one to five carbon atoms;R₁ ishydrogen, benzyl or R₁ ' wherein R₁ ' is alkanoyl having from one tofive carbon atoms, P(O) (OH)₂ and mono- and disodium and potassium saltsthereof, --CO(CH₂)₂ COOH and the sodium and potassium salts thereof; R₂and R₃ taken together are oxo or alkylenedioxy having from two to fourcarbon atoms; W is hydrogen pyridyl, or ##STR24## wherein W₁ ishydrogen, chloro or fluoro; when W is hydrogen, Z is (a) alkylene havingfrom five to thirteen carbon atoms; or (b) --(alk₁)_(m) --O--(alk₂)_(n)-- wherein each of (alk₁) and (alk₂) is alkylene having from one tothirteen carbon atoms; each of m and n is 0 or 1; with the provisos thatthe summation of carbon atoms in (alk₁) plus (alk₂) is not less thanfive or greater than thirteen; and at least one of m and n is 1; when Wis other than hydrogen, Z is (a) alkylene having from three to eightcarbon atoms; or (b) --(alk₁)_(m) --O--(alk₂)_(n) wherein each of (alk₁)and (alk₂) is alkylene having from one to eight carbon atoms; each of mand n is 0 or 1; with the provisos that the summation of carbon atoms in(alk₁) plus (alk₂) is not less than three or greater than eight; and atleast one of m and n is
 1. 2. A compound according to claim 1 wherein Ris hydroxy, and R₁ is hydrogen or benzyl.
 3. A compound according toclaim 2 wherein R₂ and R₃ taken together are oxo or alkylenedioxy.
 4. Acompound according to claim 3 wherein Z is alkylene and W is hydrogen.5. The compound according to claim 4 wherein R₁ is hydrogen; R₂ and R₃taken together are oxo; and Z is --CH(CH₃)₂ (CH₂)₆ --.